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Carbohydrate intolerance and frank diabetes mellitus (DM) are recognised features of cystic fibrosis (CF), but their cause has not been established. Damage to the islet cells due to pancreatic fibrosis is the most common explanation. The relationship between the genotype and the occurrence of diabetes mellitus has been examined in 21 cystic fibrosis patients attending our out-patient chest clinics. DNA samples were tested for the presence of the most common mutation (delta F508) and the results related to the degree of carbohydrate intolerance. We found that in CF patients over 18 years of age diabetes is more frequent among those homozygous for the delta F508 allele than the heterozygotes (P < 0.05). Those homozygous for delta F508 were diagnosed as CF at an earlier age than the heterozygotes (P < 0.05). Both the mean age and the female/male ratio were similar in the diabetic and non-diabetic groups. The prevalence of the delta F508 allele was similar to that expected in a random sample of East Anglian cystic fibrosis patients. These data suggest that the occurrence of diabetes mellitus in patients with cystic fibrosis is related to the genotype, which could be secondary to the way the genetic factors influence the degree of pancreatic disease and its rate of progression.
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PMID:Genotype analysis in cystic fibrosis in relation to the occurrence of diabetes mellitus. 768 8

Children with chronic illness live with the specific consequences of their illness, as well as secondary endocrine abnormalities that further compromise growth and pubertal development. These secondary abnormalities may significantly add to their physiologic and psychological burden. Although these endocrine abnormalities theoretically arise as adaptations to the chronic illness, they may have deleterious effects if they persist untreated. Children with HIV infection and other wasting disorders, for example, show growth suppression out of proportion to the severity of their primary illness as a result of growth hormone resistance and enhanced cortisol secretion. In hematologic conditions such as sickle cell anemia, thalassemia, or bone marrow transplant, damage to the hypothalamus and/or pituitary may lead to growth hormone deficiency, gonadal insufficiency, and hypothyroidism. Growth and pubertal delay are also common among children with cystic fibrosis, along with insulin-dependent diabetes mellitus caused by pancreatic fibrosis. Similarly, children receiving long-term steroid therapy have delays in growth and pubertal development, accompanied by risk for osteoporosis, whereas chronic renal disease is associated with growth and pubertal delay, as well as secondary hyperparathyroidism. Recognition of potential endocrinopathies in children with chronic illness is an important aspect of the care of these children because the disturbances are frequently amenable to treatment, permitting full or partial restoration of normal growth and development in these children. In this chapter, the endocrine consequences of common chronic conditions of childhood are reviewed, as well as the etiology of the endocrine disturbance, the clinical consequences, and recommendations for treatment.
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PMID:Advances in the recognition and treatment of endocrine complications in children with chronic illness. 1064 63

It is hoped that, in this millennium, chronic pancreatitis will be diagnosed earlier in the course of the disease process. Improved axial imaging of the pancreatic duct and pancreatic parenchyma will diminish the need for other invasive tests. Surgical procedures are directed at pancreatic duct decompression or resection of the pancreas (head, body or tail) or, infrequently, total pancreatectomy. Pain relief in 75% to 90% is the general rule, with diabetes developing subsequently in as many as 33% of patients. Surgery for chronic pancreatitis is effective in correcting sequelae of pancreatic fibrosis. Endoscopic stenting of the pancreatic and bile duct is used more frequently today. Until their place is ascertained, careful performance of surgery will continue to be a mainstay of treatment.
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PMID:Surgery and chronic pancreatitis. 1139 30

Associated visceral organ involvement evidence by systemic fibrosis has not been explored in oral submucous fibrosis (OSF). The investigations in this aspect were limited to loco-regional sites of naso/oropharynx and oesophagus. The study of whether the oral fibrosis is part of a systemic spectrum of disease involving multiple organs is an interesting pursuit. With this intention the patients diagnosed on clinical and histological grounds for OSF were concurrently tested by biophysical means for the presence of endomyocardial fibrosis (EMF), pancreatic (PF) and retroperitoneal fibrosis (RPF), which are endemic to the area studied. Twenty-five (n = 25) cases of OSF who visited the Department of Oral pathology & Microbiology. Govt. Dental College, Trivandrum, India for symptomatic relief of their illness comprised the study group. Ten (n = 10) age and sex matched healthy volunteers comprised the control. All the subjects have had undergone cardiologic and gastrointestinal investigations to rule out the possibility of concurrent EMF and PF. The patients were all of Indian ethnic extraction and mostly (> 90%) were from low socio economic classes. The mean age of the patients was 54.16 +/- 14.6 years, including 18 females and 7 males (F:M = 2.57:1). The severity of fibrosis was unrelated to the age of patients (P > 0.05). All the patients were chewers of areca quid (12%)/tobacco (88%). In addition to quid chewing 3/25 (12%) patients smoked 'bidi' and 6/25 (24%) consumed home brewed liquor (arrack/toddy) which contain about 40-50% ethanol. Statistically no relationship was observed between the clinical stages of OSF and severity of epithelial dysplasia in this study (P > 0.05). Out of the 25 patients, 5 (20%) showed sclerotic aortic value which may be an age related finding. Also 7 (28%) patients were found to be hypertensive and interstitial lung disease was present in 2 (8%). The possibility of EMF in one female patient who showed thickened RV apical endocardium was ruled out by cardiac catheterisation. Thus none of the patients showed evidence of endomyocardial fibrosis. The pancreas was found to be hyperchoic in 8(32 1/4) by ultra sonography. Liver was found to be hyperchoic in 6 (24%). Fat stain in stool samples was found to be positive in 13(58%). The hyperchogenecity of pancreas may be due to alcoholism or an underlying endocrine pancreatic insufficiency like diabetes and not due to pancreatic fibrosis. The positivity of fat stain could be due to fatty liver/alcoholism. Thus the study fails to reveal any evidence of pancreatic fibrosis in the group. The lack of any evidence of an associated visceral organ fibrosis in OSF made it prudent to believe that this is a loco-regional disease, initiated by local factors and propagated under their influence without systemic involvement.
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PMID:Visceral organ involvement is infrequent in oral submucous fibrosis (OSF). 1144 4

The aim of this study was to establish if the changes in the ultrastructure of the exocrine part of the pancreas are correlated with changes in serum glucose, cholesterol and lipoprotein fractions during the progression of diabetes in rabbits. Diabetes mellitus was induced in male New Zealand rabbits by a single injection of alloxan into the auricular vein. On the day 7th the glucose level in the whole blood was measured and this day was designated as the first day of diabetes. Rabbits were divided into 5 groups: untreated control, 21-day diabetes, 42-day diabetes, 90-day diabetes and 180-day diabetes. The cholesterol, HDL (high-density lipoprotein) and LDL (low-density lipoprotein) levels were examined in the serum. The total pancreatic lipase activity was measured spectrophotometrically in the pancreatic homogenate. Histological specimens were examined under an electron microscopy. The glucose level increased significantly in all of the alloxan exposed animals. The significant elevation of cholesterol level was observed on day 21 and 180. The HDL level was increased (P<0.05) only on the day 21st. The LDL level and the total activity of pancreatic lysosomal lipase increased significantly on day 21, 42 and 90. Further dilation of granular endoplasmic reticular ducts and decrease in the number of zymogen granules were observed amongst exocrine cells. Fragmented mitochondrial and translucent matrix were also seen. Intensification of the pancreatic fibrosis was found on day 90. Microvascular changes were reported in exocrine cells after 180 days. Their nuclei were smaller with large bulges on the nuclear membrane, and the number of heterogeneous electron granules of zymogen further declined. We concluded that the intensification of ultrastructural changes of the exocrine part of the pancreas correlated with the changes of the pancreatic lipase activity, and glucose and lipoprotein levels.
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PMID:Lipid and exocrine pancreatic ultrastructural changes due to experimental diabetes. 1181 48

Recently established Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of naturally occurring obesity diabetes, exhibit progressive accumulation of connective tissue in the pancreas. The present study was designed to determine the pathogenic role of transforming growth factor-beta1 (TGF-beta1) in the development of pancreatic fibrosis in OLETF rats by investigating the serial changes in the expression of TGF-beta1 and extracellular matrix (ECM) in the pancreas. Progressive proliferation of connective tissue arose from the interstitial region surrounding islets at 20 wk of age and extended to the exocrine pancreas adjacent to the islets. TGF-beta1 mRNA levels in the pancreas increased at 20 wk of age and reached a peak value at 30 wk of age. Fibronectin (FN) and procollagen types I and III mRNAs peaked at 20 wk of age and remained at higher levels than those in the nondiabetic counterparts Long-Evans Tokushima Otsuka rats until 50 wk of age. Immunoreactivities for TGF-beta1 and FN were found in islets of OLETF rats at 20 wk of age and were seen in acinar and interstitial cells at 50 wk of age. Moreover, alpha-smooth muscle actin was located at interstitial region surrounding the islets. Proliferation of the connective tissue in the pancreas of OLETF rats closely correlated with expression of TGF-beta1 and ECM. Our results suggest that the development of pancreatic fibrosis in OLETF rats extends from endocrine to exocrine pancreas and that TGF-beta1 is involved in pancreatic fibrosis of OLETF rats.
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PMID:Role of TGF-beta1 in the development of pancreatic fibrosis in Otsuka Long-Evans Tokushima Fatty rats. 1184 6

Alcoholic pancreatitis is a major complication of alcohol abuse. Until recently, it was generally accepted that alcoholic pancreatitis was a chronic disease from the outset. However, evidence is now emerging in support of the 'necrosis-fibrosis' hypothesis that alcoholic pancreatitis begins as an acute process and that repeated episodes of acute injury lead to the changes of chronic pancreatitis (acinar atrophy and fibrosis) resulting in exocrine and endocrine dysfunction. The treatment of acute pancreatitis follows the regimen of bed rest, nasogastric suction, analgesia and intravenous support. The role of additional therapeutic measures such as prophylactic antibiotics, antioxidants and enteral nutrition in severe cases has not yet been precisely defined. The treatment of chronic pancreatitis involves attention to its three cardinal features: pain, maldigestion and diabetes. With respect to the pathogenesis of alcoholic pancreatitis, the focus of research over the past 30 years has shifted from the sphincter of Oddi and ductular abnormalities to the acinar cell itself. It has now been established that the acinar cell is capable of metabolizing alcohol and that direct toxic effects of alcohol and/or its metabolites on acinar cells may predispose the gland to injury in the presence of an appropriate trigger factor. A significant recent development relates to the characterization of pancreatic stellate cells, increasingly implicated in alcoholic pancreatic fibrosis. This chapter summarizes the natural history, clinical features, current trends in treatment as well as recent advances in our understanding of the pathogenesis of alcoholic pancreatitis.
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PMID:Alcohol-induced pancreatic injury. 1282 57

Islet amyloid has been suggested to be an important link between insulin resistance and beta-cell dysfunction in type 2 diabetes. To investigate the prevalence and clinicopathological characteristics of islet amyloid, we examined consecutive autopsies of 235 Chinese patients with type 2 diabetes and 533 nondiabetic subjects. Islet amyloid deposits were identified using Congo red staining and quantitated by image analysis. We found that 3.0% of the nondiabetic subjects versus 39.6% of the diabetic patients displayed islet amyloid (P < 0.001). In diabetic patients, the amyloid deposits occupied a mean islet area of 36.2%, which was positively associated with BMI, blood pressure, and glycemic control. Pancreatic fibrosis and fat infiltration were more frequently found in diabetic patients with islet amyloid than those without islet amyloid, whereas pancreatic arteriosclerosis was identified in all diabetic patients. These findings suggest that islet amyloid deposits reflect greater insulin resistance and islet failure in a subgroup of type 2 diabetic patients. Islet failure may also have been exacerbated by fat infiltration, fibrosis, and arteriosclerosis. Optimal blood pressure and metabolic control may reduce these pathological changes and help preserve islet cell mass.
Diabetes 2003 Nov
PMID:Prevalence and clinicopathological characteristics of islet amyloid in chinese patients with type 2 diabetes. 1457 94

Diabetes mellitus (DM) and abnormal glucose tolerance (IGT) are common in cystic fibrosis (CF). The loss of pancreatic beta-cells due to pancreatic fibrosis is thought to be one of the principal causes of diabetes in CF, but the aetiology of DM remains somewhat puzzling. Genetic factors may contribute to the development of CF related diabetes (CFRD). The purpose of this study was to investigate the role of polymorphisms in six genes on IGT or DM incidence. PCR and dHPLC were used to screen DNA samples for polymorphisms. Using 2-h oral glucose tolerance tests, 163 adult pancreatic insufficient CF patients have been subdivided in 3 groups: 54 NGT (normal glucose tolerance), 33 IGT and 76 CFRD. We found the first evidence for the association between CFRD and UCSNP-19 polymorphism in the CAPN10 gene. The UCSNP-19 genotype distribution differed significantly between NGT, IGT and CFRD groups. The difference reflected an increase in the 22 genotype (3 copies of 32-bp sequence) in IGT and CFRD patients (p=0.05). Odds ratio for the homozygote 22 versus homozygote 11 was 3.4 (p=0.02). All allele and genotype distributions for the other polymorphisms were similar in the three groups. In conclusion, our observations suggest that UCSNP-19 of CAPN10 may be involved in the pathogenesis of diabetes in CF.
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PMID:Calpain 10 and development of diabetes mellitus in cystic fibrosis. 1637 60

Cystic fibrosis is an autosomal recessive disorder affecting about 1/3500 case in France. The disease, that affects all epithelia, is responsible for pulmonary tract infections but also pancreas, gut, liver and genital tract abnormalities. It is linked to CFTR gene mutations, inducing unusually high increase of sodium chloride in sweat, used to track down the illness. deltaF508 CFTR mutation, encountered in 70% of cases, is nearly always associated to pancreatic insufficiency with early-onset lung attack. Around 10% of cystic fibrosis cases, whatever the age, are complicated with partially insulinopenic diabetes, favored by pancreatic fibrosis, while one third of patients shows glucose intolerance. After 20 years old, one third of patients suffers from diabetes and one half after 30 years. Diabetes diagnosis is difficult, and requires the fulfillment of oral glucose tolerance test (OGTT). One glycemia greater or equal to 2 g/l, two hours after a 75 g glucose load, established diabetes diagnosis. Indeed, fasting blood glucose and glycated hemoglobin appear as poor diagnosis markers. Despite histological arguments in favor of the mainly mechanical islet disturbances, an increased prevalence of anti-islets auto-antibodies and an increased frequency of HLA DR3/DR4 have been reported in cystic fibrosis population with glucose tolerance troubles. Also, glucose metabolism is influenced by specific factors linked to cystic fibrosis (infection, malnutrition, steroids...). In reason of the silent phase of diabetes, systematic tracking down of diabetes with a yearly OGTT is recommended, all the more so that hyperglycemia appears as a worsening factor of cystic fibrosis. The efficacy of oral anti-diabetic drugs has not been evaluated on large studies. By contrast, some studies argue for insulin therapy as soon as diabetes appears, insulin improving respiratory and nutritional prognosis. In conclusion, the aim of treatment of cystic fibrosis is to prevent the lung function decline by controlling inflammation and infection, to implement endo- and exo-crine pancreas insufficiency, and to improve nutritional status.
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PMID:[Cystic fibrosis diabetes in adult]. 1639 85


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