What is the function of the pancreas and how are its disorders managed?

The Pancreas: Structure, Function, and Disorder Management

Dual Functional Architecture

The pancreas serves as a central metabolic regulator with two distinct but interconnected functions: exocrine secretion of digestive enzymes and endocrine hormone production for glucose homeostasis. 1, 2

Exocrine Function

• The pancreas secretes over 10 different digestive enzymes along with water, bicarbonate, and enzyme inhibitors that hydrolyze lipids, proteins, and carbohydrates in the intestinal lumen. 1
• Enzyme output reaches maximum rates following a mixed meal of 20 kcal/kg body weight, with duration increasing based on caloric load. 1
• The quantity of enzymes secreted far exceeds the minimal amount required to prevent nutrient malabsorption. 1
• Pancreatic secretion is tightly coordinated with gastric emptying and duodenal nutrient delivery, occurring both postprandially and during fasting states. 1

Endocrine Function

• The endocrine pancreas consists of islets of Langerhans organized with insulin-producing β-cells in the core, surrounded by glucagon-producing α-cells, somatostatin-producing δ-cells, pancreatic polypeptide-producing cells, and ghrelin-producing cells. 3
• β-cells are the only cells in the body capable of producing and secreting insulin to regulate nutrient absorption after meals. 4
• Extensive paracrine crosstalk between β-cells, α-cells, and δ-cells ensures precise insulin release matched to metabolic need, maintaining stable blood glucose levels over decades. 4
• The pancreas orchestrates endocrine hormone secretion in response to glucose, lipids, amino acids, hormones, and inflammatory signals. 5

Pancreatic Disorders and Their Management

Diseases of the Exocrine Pancreas Leading to Diabetes

Any process that diffusely injures the pancreas can cause diabetes, termed pancreatic diabetes or pancreoprivic diabetes (formerly "type 3c diabetes"). 1

Etiologies Include:

• Pancreatitis (acute and chronic), trauma, pancreatectomy, pancreatic carcinoma, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy, and idiopathic forms. 1
• Damage must be extensive for diabetes to occur, except with pancreatic cancer where even small adenocarcinomas can cause diabetes through mechanisms beyond simple β-cell mass reduction. 1
• Approximately 25% of patients develop diabetes or prediabetes following acute pancreatitis. 6

Diagnostic Features:

• Concurrent pancreatic exocrine insufficiency documented by monoclonal fecal elastase 1 test or direct function tests. 1
• Pathological pancreatic imaging findings on endoscopic ultrasound, MRI, or CT. 1
• Absence of type 1 diabetes-associated autoimmunity. 1
• Loss of both insulin and glucagon secretion with often higher-than-expected insulin requirements. 1
• "Brittle" diabetes with erratic blood glucose swings due to combined loss of insulin and counter-regulatory hormones. 6

Management Approach:

• Individualized medical nutrition therapy with regular blood glucose monitoring is essential. 6
• Treatment must address both hyperglycemia and underlying pancreatic conditions concurrently. 6
• Management is complicated by malabsorption from exocrine dysfunction and poor dietary intake from chronic abdominal pain. 6
• For pancreatectomy cases, islet autotransplantation can retain insulin secretion, potentially achieving insulin independence or reducing insulin requirements. 1

Genetic Defects of β-Cell Function (MODY)

Maturity-onset diabetes of the young (MODY) results from monogenetic defects in β-cell function, characterized by hyperglycemia onset before age 25 years with impaired insulin secretion and minimal insulin resistance. 1

Key Features:

• Autosomal dominant inheritance pattern with abnormalities at six genetic loci identified. 1
• Most common form involves mutations in hepatocyte nuclear factor (HNF)-1α on chromosome 12. 1
• Second form involves glucokinase gene mutations on chromosome 7p, affecting the β-cell "glucose sensor." 1
• Less common forms result from mutations in HNF-4α, HNF-1β, insulin promoter factor (IPF)-1, and NeuroD1. 1

When to Suspect MODY:

• Diabetes diagnosed within the first 6 months of life (with occasional later presentations, mostly INS and ABCC8 mutations). 1
• Diabetes without typical type 1 or type 2 features: negative diabetes-associated autoantibodies, non-obese, lacking metabolic features, especially with strong family history. 1
• Stable mild fasting hyperglycemia (100-150 mg/dL), stable A1C between 5.6-7.6% (38-60 mmol/mol), especially if non-obese. 1
• Refer suspected cases to specialists for genetic testing, which is increasingly cost-effective and can guide treatment for affected family members. 1

Endocrinopathies Causing Diabetes

Hormones including growth hormone, cortisol, glucagon, and epinephrine antagonize insulin action; their excess causes diabetes in individuals with preexisting insulin secretion defects. 1

• Acromegaly (growth hormone excess), Cushing's syndrome (cortisol excess), glucagonoma, and pheochromocytoma can precipitate diabetes. 1
• Somatostatinoma and aldosteronoma-induced hypokalemia cause diabetes partly by inhibiting insulin secretion. 1
• Hyperglycemia typically resolves when hormone excess is corrected or tumor is successfully removed. 1

Drug- or Chemical-Induced Pancreatic Dysfunction

Many drugs impair insulin secretion or action, precipitating diabetes in susceptible individuals with insulin resistance. 1

High-Risk Medications:

• Corticosteroids, thiazide diuretics, beta-blockers, estrogen therapy, antipsychotics, immunosuppressants, and antiretroviral protease inhibitors. 7
• Nicotinic acid and glucocorticoids impair insulin action. 1
• β-interferon can cause diabetes with islet cell antibodies and severe insulin deficiency. 1
• Certain toxins (Vacor rat poison, intravenous pentamidine) permanently destroy pancreatic β-cells, though these reactions are rare. 1

Hyperglycemia-Induced Pancreatic Damage

Oxidative damage from hyperglycemia contributes to impaired pancreatic β-cell function and exacerbates insulin resistance, creating a vicious cycle. 6

• Hyperglycemia-induced pancreatic injury can develop into pancreatic diabetes with both structural and functional loss of insulin secretion. 6
• Prevention requires aggressive glycemic control to interrupt the cycle of hyperglycemia-induced β-cell damage. 6

Fatty Pancreas (Pancreatic Steatosis)

Hypertriglyceridemia is strongly associated with pancreatic steatosis, with elevated triglycerides and free fatty acids causing direct toxicity to pancreatic acinar cells and capillary membranes. 7

Contributing Factors:

• Weight gain, lack of exercise, diet rich in simple carbohydrates, and excessive alcohol intake. 7
• Untreated or poorly controlled diabetes with hyperglycemia and hyperinsulinemia. 7
• Metabolic syndrome components: central obesity, hypertension, abnormal glucose metabolism. 7
• Genetic disorders affecting lipid metabolism (familial hypertriglyceridemia, familial combined hyperlipidemia). 7

Common Pitfalls and Caveats

• Pancreatic diabetes is commonly misdiagnosed as type 2 diabetes; always assess for pancreatic exocrine insufficiency and obtain pancreatic imaging when diabetes presents atypically. 1
• Do not assume all young-onset diabetes is type 1; consider MODY when autoantibodies are negative and family history is strong. 1
• Approximately 30% of acute pancreatitis patients are already malnourished at presentation, requiring early nutritional assessment. 1
• Risk for microvascular complications in pancreatic diabetes is similar to other diabetes forms despite different pathophysiology. 1
• The presence of autoantibodies in patients with monogenic diabetes has been reported, so their presence does not absolutely exclude MODY. 1