Keywords:Chapter 15, Pancreas and Diabetes

Abnormal insulins
Defective insulin molecules(B 25 F--> L, B 24 F-->S)

Incomplete conversion of pro-insulin(10% of biological insulin action) to insulin.
Acute pancreatitis
Most commonly caused by alcoholism, impacted gallstones and hyperlipidemia. Zymogens in acinar cells are activated by interaction with bile salts or small bowel brush-border enterokinase, causing autodigestion of pancreas and surrounding organs. The majority of cases are acute edematous, interstitial pancreatitis, whereas 5% are the more serious form, acute hemorrhagic pancreatitis.
Adenocarcinoma of pancreas
Most tumors are ductal cell carcinoma (>90%) with a very poor prognosis of 1% 5 year survival. It has perhaps the worst prognosis of any tumor, due largely to its anatomical location. Head portion tumors account for 2/3 of cases, and present with biliary obstruction, whereas body and tail portion tumors account for 1/3 of cases and present with insidious onset with late stage dissemination. Smoking and high fat diet appear to increase the incidence. Pancreatic adenocarcinoma does not respond well to chemotherapy or radiotherapy. The therapy of choice is surgery (the Whipple procedure), which includes removal of the pancreas, duodenum, and a portion of the stomach. Operative mortality is quite high.
Amyloidosis of islets
a common finding in older patients with type 2 diabetes. Beta cells are well preserved.
C-peptide
proinsulin (9K Da) consists of single-chain peptide(A and B chains and C-peptide) and is cleaved to insulin(6 K Da) and C-peptide(3 K Da) by convatase at an equimolar amounts. In type 1 diabetics, endogenous insulin synthesis is absent and C-peptide is also absent in the serum. Radioimmunoassay of serum C-peptide in response to astronaut's diet thus indicates endogenous insulin synthesis. In normals and type 2 diabetics, serum C-peptide is more resistant in breaking down than insulin, thus serum C-peptide levels are higher than that of insulin.
CFTR(CF transmembrane conductase regulator=cAMP dependent chloride channel pump)
The protein consists of two transmembrane domains, two nucleotide-binding domains and a regulatory domain, containing protein kinase A and C phosphorylation sites. Among 200 mutations of CF gene, 70% is a deletion of three nucleotide coding phenylalanine at amino acid position 508(DF 508), which represents clinically severe CF. Other mutaions represent less severe CF. The D F 508 mutation results in defective processing of CFTR protein, which does not become fully glucosylated and is degraded before it reaches the cell surface. The heterozygous carries of DF 508 have one half of normal CFTR and do not present clinical symptoms.
Chronic relapsing pancreatitis
progressive destruction of pancreas by repeated mildly symptomatic pancreatitis. Irregularly distributed fibrosis with decreased acinar tissue. Clinically presents with recurrent abdominal pain and pancreatic exocrine insufficiency with steatorrhea and weight loss. Calcification in pancreas by X-ray or CT scan.
Coronary heart disease in diabetes
coronary atherosclerosis is more diffuse in older type 2 diabetics and is the major cause of death. Silent MI is common(50%) in this group because of accompanying diabetic neuropathy compared with non-diabetic (10 %). Coronary bypass is less effective in this group.
Cystic fibrosis(CF)
The most common deadly genetic disease in U.S., autosomal recessive, heterozygous 1/25, homozygous 1/2,500, death in early life is due to GI diseases (meconium ileus and malnutrition) and in later life by chronic lung diseases (bronchiectasis and recurrent bronchopneumonia due to pseudomonas infection). The life expectancy is 24-25 years of age. The primary defect is in the regulation of epithelial chloride transport. Atrophy and necrosis of pancreatic acinar (gland) tissue occurs, whereas islet cells are usually intact.
Diabetes(siphon in Greek)
is a symptom complex characterized by chronic hyperglycemia and disturbance of carbohydrate and lipid metabolism, which are often associated with accelerated aging processes of microvascular atherosclerosis in eye and kidneys and an increased frequency of macrovascular disease--peripheral vascular and coronary heart disease.
Diabetic foot problems
Greater than 50% of non-traumatic amputations occur in DM patients and are the result of diabetic neuropathy, peripheral vascular disease and superimposed infections.
Diabetic nephropathy
The incidence is about 50% for type 1 and 5-10% for type 2 diabetes 20 years after diagnosis and is ultimate lethal complication. The onset of hypertension in type 1 diabetics is indicative for nephropathy. It presents with albuminuria, nephrotic syndrome and hypertension. A gradual increase in basement membrane (BM) becomes evident on renal biopsy after > 5 years of type 1 diabetes. This increase progresses slowly and relatively uniformly until after 10-20 years the BM is double its normal thickness when BM materials accumulates in the mesangeal zone, so that the vascular and urinary spaces become compromised. Nodular sclerosis (Kimmelstiel-Wilson) is still the hallmark of diabetic nephropathy.
Diagnosis of diabetes
Type 1: classic symptoms (polydipsia, polyphagia, polyuria) and unequivocal elevation of plasma glucose >200 mg/dl. Type 2: no symptoms but fasting plasma glucose (FPG) > 140 mg/dl on two occasions (chemical diabetes). For those with FPG >140 mg/dl: after oral glucose 75gm tolerance test(or 1.75 gm/Kg body weight), 2 hr plasma glucose >200 mg/dl and one more intervening value >200 mg/dl (at 1/2, 1 or 1 1/2 hr).
Gastrinomas (Zollinger-Ellison tumor)
presents with a classic triad of 1) non-insulinoma, 2) gastric hypersecretion, 3) severe peptic ulcer. At least 2/3 of tumors are malignant and may occur in duodenum, but not in stomach.
Glucagonomas
a triad of 1) necrolytic migratory erythema, 2) diabetes, 3) anemia.
GU system in CF
Females have normal reproductive system whereas males have discontinuity of vas deferans and are sterile.
HLA type
In type 1 diabetes, 95% are positive to either HLA-DR3 or DR-4 or both compared with 40% of general population. When both DR-3 and DR-4 are positive, diabetes occurs in families at the youngest age group.
Impaired glucose tolerance test
FPG 140 mg/dl and 2hr plasma glucose >140 mg/dl and 200 mg/dl with one intervening value >200 mg/dl after oral glucose tolerance test. About 25% of patients of this condition eventually become diabetic.
Inheritance of diabetes
Among identical twins, the concordance rate(both twins affected) is 50% in type 1 and > 90% in type 2 diabetes. The mode of type 2 diabetes is multifactorial.
Insulin receptor affinity
In Scatchard plot, the negative slope of the line (Ke). The receptor affinity decrease is noted in glucocorticoid excess, insulin resistance due to anti-receptor antibodies and in lipoatrophic diabetes.
Insulin receptor concentration
In Scatchard plot, the abcissa intercepts, Ro. The receptor concentration is decreased in obese diabetics(10-20% decrease) and in acanthosis nigricans.
Insulin receptor
A glycoprotein of 400 kDa consisting of four glycosylated peptide chains covalently linked by disulfide bonds. The molecules are a dimer consisting of two alpha-subunits(120 kDa) which include binding sites for insulin, and two beta-subunits(80 kDa), which are involved in initiating some of the insulin actions. For practical purpose, cell membrane fractions of peripheral blood monocytes are used for insulin receptor assay.
Insulin resistance
is defined as an insulin requirement of over 200 U per day for one week(normal pancreas secretes 30-50 U insulin per day). Infections and gross obesity are responsible for most cases of insulin resistance.
Insulinomas
Often present with hyperinsulinemia (Whipple triad):1) hypoglycemic attach with serum glucose 50 mg/dl, 2) symptoms of hypoglycemia-CNS symptoms, and 3) hypoglycemic attacks relieved by glucose intake. Greater than 90% of tumors are benign with relatively higher serum proinsulin levels. All other non-insulinomas are potentially malignant.
Islet cell tumors
Islet cell tumors represent a small fraction of pancreatic tumors(1-5% of all tumors) and are incidentally found in 1-2% of patients at autopsy. Relative incidence: insulinoma(75%), gastrinoma(15-20%), vipoma(1-2%), glucagonoma(1-2%), somatostatinoma( 1%), PPoma( 1%), and non-functioning tumors(1%).
Laboratory diagnosis of acute pancreatitis
elevation of serum amylase(> 400 Somogyi unit/dl) during first 24 hrs, followed by rising serum lipase levels within 72-96 hrs. Enlarged pancreas by CT scan. Markedly elevated amylase levels in ascitis.
MEA 1(Wermer syndrome)
polyendocrine involvement with peptic ulcer
gastrinoma or antrum G-cell hyperplasia, pituitary adenoma(prolactinoma) and adrenal cortical adenoma.
MEA 2(Sipple syndrome)
medullary carcinoma-pheochromocytoma syndrome without peptic ulcer. Usually bilateral medullary carcinoma of thyroid and bilateral pheochromocytomas and neuroma.
Mucinous cystadenocarcinoma
a large multiloculated tumor lined by columnar mucin-producing epithelium in 40-60 year old women. It has a better prognosis of 40-90% survival rate if resected.
Multiple endocrine adenomatosis(MEA)
an autosomal dominant disease with a high degree of penetrance. If autopsy is carefully performed, all listed organs are involved. Both MEA 1 and 2 share parathyroid hyperplasia or adenoma.
Pathogenesis of diabetic complications
is multifactorial and is accelerated aging process. Increased glucose in tissues and blood. e.g. BM, HbA1C. Increased sorbitol in tissues. e.g. diabetic nerve. Decreased intracellular myoinositol. e.g. diabetic muscle.
PPomas
presents no specific symptoms despite elevated serum pancreatic polypeptide (PP) levels.
Pseudocyst
a complication of acute and chronic relapsing pancreatitis. A psudocyst is formed by digestion of surrounding tissue by activated pancreatic enzymes, which does not have epithelial lining.
Somatostatinomas
a triad of 1) diabetes, 2) hypochlorhydria, 3) steatorrhea.
Somogyi phenomenon
Hyperglycemia and ketonuria may paradoxically occur after excessive insulin injection. Reactive hyperglycemia, known as Somogyi phenomenon, results from the release of catecholamine, cortisol, growth hormone and glucagon in response to acute hypoglycemia induced by excessive insulin injection. Patients exhibiting Somogyi phenomenon are usually type 1 diabetics who are difficult to control by single dose of insulin injection. Rx
Gradually decrease the amount of insulin by 10-20%.
Sweat chloride test
A screening test for CF. >70 mmol sweat chloride is diagnostic for CF. Normal 50 mmol/ L)
Type 1 diabetes(insulin-dependent, juvenile onset, ketosis- prone)
accounts for 10% of all cases. An abrupt onset during childhood or puberty with polydipsia, polyphagia and polyuria. Usually undernourished. Blood glucose fluctuates widely in response to small changes in insulin dosage, exercise and infection. Endogenous serum insulin is negligible or zero, thus it requires insulin replacement injection. Microvascular atherosclerosis is absent until five years or more from diagnosis.
Type 2 diabetes(insulin non-dependent, adult onset, ketosis resistant)
accounts for 90% of cases. An insidious onset after 40 years of age with no clinical symptoms. 80% is overweight. Blood glucose fluctuation is less marked. Endogenous insulin secretion is maintained but insulin receptor sites are decreased, leading to hyperglycemia. Micro- and macro-vascular atherosclerosis is present at diagnosis.
Venous thrombosis in patients with pancreatic carcinoma
Peripheral venous thrombosis occurs in about 1/4 of patients with pancreatic adenocarcinoma due to increased viscosity (Trousseau sign).
Vipoma(vasoactive intestinal polypeptide, diarrheogenic tumor)
A triad of 1) non-insulinoma, 2) watery diarrhea (10-20 gallon/day), 3) hypokalemia and achlorhydria (WDHA syndrome).
Zollinger-Ellison syndrome
Z-E syndrome refers to hypergastremia due to antrum G-cell hyperplasia. It presents with a shorter history of peptic ulcer and higher serum gastrin levels.