📘 Understanding pancreatic diabetes mellitus

Diabetes secondary to pancreatic diseases occurs when a pancreatic condition destroys both exocrine function (production of digestive enzymes) and endocrine function (production of insulin, glucagon and other hormones) [1]. Main causes include chronic pancreatitis, severe acute pancreatitis, pancreatic cancer, cystic fibrosis, hemochromatosis and pancreatic surgeries. Unlike type 1 diabetes (autoimmune) or type 2 (insulin resistance), endocrine cell destruction (alpha, beta, etc.) results from the pathological process of that pancreatic disease.

This form of diabetes represents 5-10% of all diabetes cases, but is frequently misdiagnosed as type 2 diabetes [1]. Simultaneous loss of glucagon secretion (from alpha cells) makes blood glucose very unstable, with increased risk of severe hypoglycemia [2]. In addition, associated exocrine pancreatic insufficiency requires supplementation with digestive enzymes for proper nutrient absorption.

Chronic pancreatitis causes diabetes through progressive replacement of normal pancreatic tissue with fibrous and scar tissue [3]. Persistent inflammation gradually destroys the islets of Langerhans, where beta cells (insulin producers) and alpha cells (producers of glucagon) are located. The process is gradual, and diabetes usually appears after years of chronic pancreatitis evolution, as functional pancreatic tissue decreases significantly.

The frequency of diabetes in chronic pancreatitis is generally 30% of cases, increasing proportionally with disease duration and severity [4]. The cause of pancreatitis influences the risk of diabetes. Hereditary and alcoholic forms have higher rates of progression to diabetes [5]. Pancreatic calcifications and surgical interventions for complications accelerate endocrine function loss. Patients with chronic pancreatitis should have annual diabetes screening.

Pancreatic cancer causes diabetes through two main mechanisms. The first is the physical destruction of the islets of Langerhans by the growing tumor mass and by the inflammatory process around the tumor [6]. The second mechanism, more important, involves substances produced by the tumor, which interfere at a distance with insulin secretion and action. Studies show that blood glucose changes and unexplained weight loss may precede pancreatic cancer diagnosis by 2-3 years [6].

New-onset diabetes in people over 50 years old, without classic risk factors for type 2 diabetes, should raise suspicion of pancreatic cancer [7]. Some of the people with newly diagnosed diabetes at this age have undiscovered pancreatic cancer. The combination of recent diabetes, weight loss and low level of fecal elastase significantly increases the probability of an underlying cancer and requires prompt imaging investigations.

Type 3c diabetes (or pancreatogenic diabetes) is the term used for diabetes caused by exocrine pancreatic diseases [8]. Diagnostic criteria include the presence of a documented pancreatic disease (chronic pancreatitis, pancreatic resection, cancer, cystic fibrosis), absence of type 1 diabetes-specific autoantibodies and evidence of exocrine pancreatic insufficiency. Low level of fecal elastase confirms exocrine function impairment [1].

Signs that suggest type 3c diabetes include history of pancreatitis or pancreatic surgery, large glycemic variability with frequent episodes of hypoglycemia, low C-peptide (indicating reduced insulin reserve) and digestive symptoms such as steatorrhea (loose stool with lots of fats) or abdominal pain [9]. This diagnosis is important because diabetes treatment differs from the classic one. You frequently need insulin from the beginning, pancreatic enzymes, fat-soluble vitamins and more careful monitoring for the risk of hypoglycemia [2].

Cystic fibrosis affects the pancreas even from intrauterine life, through the production of viscous secretions that block the pancreatic ducts [10]. This obstruction leads to progressive destruction of exocrine tissue (which produces digestive enzymes) and, later, of endocrine tissue (the islets of Langerhans). Approximately 85% of people with cystic fibrosis have exocrine pancreatic insufficiency already at birth or in the first years of life.

Cystic fibrosis-related diabetes (CFRD) occurs in 20% of adolescents and 40-50% of adults with this disease [11]. In CFRD, insulin secretion deficiency predominates (similar to type 1), but there may also be a degree of insulin resistance in periods of infection or treatment with glucocorticoids [10]. Annual screening with oral glucose tolerance test is recommended starting from age 10. Insulin is the treatment of choice.

The probability of developing diabetes after pancreatectomy depends on the amount of pancreatic tissue removed [12]. Total pancreatectomy leads to diabetes in 100% of cases, because you completely remove the insulin-producing beta cells. Partial pancreatectomy leads to diabetes in 20-50% of cases, depending on the type and extent of resection, location and condition of the remaining pancreas [13].

Pancreatic tail resection affects the islets of Langerhans more, which are more concentrated in this area and involves a higher risk of diabetes [12]. A pancreas already affected by chronic pancreatitis or fibrosis more frequently develops diabetes after any surgical intervention [13]. Postoperative glycemic control can be difficult due to simultaneous loss of glucagon secretion, which increases the risk of severe hypoglycemia.

Hemochromatosis determines excessive iron accumulation in various organs, including the pancreas, where iron deposits preferentially in beta cells [14]. Excess iron generates free radicals (causes cell destruction), causing severe oxidative stress. This toxic process progressively destroys insulin-producing cells and leads to irreversible pancreatic fibrosis.

Diabetes occurs in 20-50% of patients with untreated hemochromatosis, with the highest percentage in those with severe liver damage (cirrhosis) [14]. It is traditionally called "bronze diabetes" due to associated skin pigmentation. Iron deposition also affects hepatic insulin sensitivity, adding a component of resistance to insulin action [15]. Early diagnosis and treatment of hemochromatosis can prevent or slow progression to diabetes, but already installed pancreatic lesions are usually permanent.

Yes, acute pancreatitis can lead to permanent diabetes in approximately 20-40% of cases, depending on severity and follow-up duration, especially after severe, necrotizing episodes [16]. Extensive necrosis of pancreatic tissue irreversibly destroys beta cells from the islets of Langerhans. The risk increases proportionally with the severity of the acute episode and with the need for surgical intervention for debridement (local cleaning) [17].

Diabetes can appear immediately after the acute episode or can develop in the months and years following, as fibrosis replaces normal pancreatic tissue [16]. Patients who have repeated episodes of acute pancreatitis have higher cumulative risk of diabetes. Blood glucose monitoring is recommended for at least five years after a severe episode of acute pancreatitis, for early diabetes detection.

Pancreatic diabetes (type 3c) has a distinct mechanism from types 1 and 2 [1]. In type 1, beta cell destruction is autoimmune, and in type 2 insulin resistance predominates. In type 3c diabetes, beta cell loss is due to the underlying pancreatic disease such as chronic pancreatitis, pancreatic cancer or cystic fibrosis.

An important feature of pancreatic diabetes is simultaneous loss of glucagon, which determines increased risk of severe hypoglycemia and large glycemic fluctuations [2]. Patients frequently also have exocrine pancreatic insufficiency with steatorrhea and malabsorption [8]. Type 1 diabetes-specific autoantibodies are absent, and C-peptide is variable, depending on the remaining beta cell mass.

To confirm the pancreatic origin of diabetes, the doctor will request several categories of investigations [3]. Abdominal imaging by CT or MRI can show pancreatic calcifications, atrophy, pseudocysts or ductal changes suggestive of chronic pancreatitis. Endoscopic ultrasound offers additional details about parenchyma and pancreatic ducts.

Exocrine function tests such as fecal elastase confirm exocrine pancreatic insufficiency [1]. Low levels of fat-soluble vitamins (A, D, E, K) suggest malabsorption from exocrine pancreatic insufficiency. Type 1 diabetes-specific autoantibodies are negative. C-peptide can be low or normal, depending on residual beta cell reserve [9].