Type 3c Diabetes

Type 3c is an emerging subtype of diabetes mellitus. Although it is not currently clinically recognised by the World Health Organisation (WHO), it is a serious chronic condition in which the pancreas is damaged and produces less of the vital hormone insulin, as well as other important secretions?  The pancreas is a complex 15 cm-long organ near the stomach, consisting of the Islets of Langerhans and Acinar tissue, and connected to the gut via an array of ducts.  It has both endocrine (islet-mediated, blood sugar-related) and exocrine (acinar-mediated, digestion-related) secretory functions. Type 3c diabetes is also known as pancreatogenic diabetes because it is frequently seen in cases of chronic pancreatitis (chronic pancreatic inflammation), pancreatic cancer, cystic fibrosis and haemochromatosis, which damage the pancreas and impair its exocrine function. 

The global health crisis that is diabetes continues to grow and it can no longer be considered rare.  It is now thought that about 8-9% of all men and 7.9% of all women in the UK have diabetes and that, disturbingly, about half of these are undiagnosed (diabetes.org.uk, Pancreapedia, European Society of Cardiology). 

What is diabetes?

Diabetes’ main feature is a lack of insulin due to reduced or absent secretion by the pancreas. This leads to higher-than-normal blood glucose levels (hyperglycaemia) and eventually a range of complications including heart, kidney and eye problems.  Insulin is a peptide hormone whose main functions are to maintain blood glucose in the normal range (3.5-7 mmol/l, 70-140 mg/dl) and to help the body’s cells take up glucose from the blood and utilise it to release energy from our food.  According to Diabetes UK, the main types of diabetes are Type 1 (aka juvenile or Insulin-dependent diabetes ([IDDM]), Type 2 (aka adult-onset or non-insulin-dependent diabetes [NIDDM]) and gestational diabetes, which sometimes occurs during pregnancy.  

Type 1 diabetes is caused by the autoimmune destruction of β-cell (Beta-cell) structures in the insulin-secreting Islets of Langerhans in the pancreas, cutting off the body’s supply of the vital hormone. This frequently occurs in children and young people, however the reason is not well understood, but it may include genetic factors and some viruses. 

Type 2 diabetes is caused by a phenomenon called insulin-resistance, where mechanisms which regulate blood glucose (in response to insulin) require a higher level of insulin than normal in order to function.  This is coupled with a decline in the ability of β-cells to produce insulin.  Type 2 diabetes results from a combination of genetic and lifestyle factors such as obesity and high cholesterol and seems to primarily affect older people. Type 2 diabetes frequently progresses to a point where insulin therapy is required.  

In terms of prevalence, Type 1 accounts for about 8% of all diabetes cases, Type 2 for 90%, and other, rarer forms for about 1-2%. The latter category can include drug-induced diabetes, Maturity Onset Diabetes of the Young (MODY) or Latent Autoimmune Diabetes in Adults (LADA).  To these historically recognised forms of diabetes must now be added Type 3.  

So, what is Type 3c Diabetes?

Type 3c diabetes was a term originally proposed to explain the connection between Alzheimer’s disease and insulin resistance in the brain.  However, it has now been applied more broadly.  It is broken down into Types 3a-3h. Type 3c (or pancreatogenic diabetes), is the name for a form of diabetes that develops from  damage to the exocrine pancreas by one to several  causes, most commonly, chronic pancreatitis (Hart et al. 2016) or pancreatic cancer;it is thus sometimes also called secondary diabetes. It can also occur after surgery on or removal of the pancreas.  

Misdiagnosis of Type 3c (as with Type 1 or Type 2) diabetes may be relatively common and, in reality, Type 3c could account for anything up to 9% of all diabetes cases, with fewer than 3% of Type 3c patients being accurately diagnosed,  according to a study by Woodmansey et al. and in data from the American Diabetes Association (ADA). (Woodmansey et al. 2017) These papers report that diabetes following pancreatic disease was classified as Type 1 5-10% of the time, and as Type 2 85-90% of the time, depending on the diagnostician.  This is not to say that all such diagnoses are inaccurate: indeed, Type 2 is common enough that it can also occur in patients with pancreatic diseases.  Type 3c is marked by a failure of the pancreas to produce sufficient levels of insulin due to damage to the β-cells.  It may also result in a condition called exocrine insufficiency, where the pancreas is so damaged by disease or other causes, that it no longer produces all of the minerals and enzymes vital for us to digest food properly (Diabetes UK).  This can increase the risk of malnutrition.

The median age at diagnosis of Type 3c is 59 years with a mean BMI of 29.2, so patients are rarely obese, unlike those with Type 2 (Woodmansey et al. 2017, American Diabetes Association).

What are the causes of pancreatic damage Type 3c diabetes?   

The most common cause by far is chronic pancreatitis (79% of Type 3c cases). This condition can be caused by alcohol, smoking, genetics, and other factors. Pancreatic inflammation damages the β-cells of the islets, among many other cells, and impairs insulin production, as well as damaging the exocrine functions of the pancreas, e.g., digestive enzyme secretion. Pancreatic cancer (predominantly Pancreatic Ductal Adenocarcinoma or PDAC, an aggressive tumour-type and the 4^th deadliest cancer overall [Pancreapedia]), accounts for about 8% of Type 3c cases. It is thought that this type of cancer causes diabetes due to its links to several forms of pancreatitis and pancreatic infections:

• One example of this is Helicobacter pylori, the organism involved in many inflammatory bowel conditions. 
• Furthermore, Haemochromatosis is a genetic disorder where excess iron builds up in the body.  This is extremely toxic to a wide range of organs and tissues, including the pancreas and has been linked to diabetes. About 7% of patients with Type 3c diabetes have haemochromatosis.
• Cystic fibrosis (CF) is a complex multifactorial, multi-tissue genetic disorder. It is thought to cause scarring of the pancreatic ducts by excess sticky mucus accumulation, and thus impair pancreatic function. It accounts for about 4% of Type 3c cases.  Those with CF-related diabetes may not knowingly experience any diabetes symptoms, since many overlap with those of CF (Hart et al. 2016).

What are the Symptoms of Type 3c Diabetes?

Symptoms of Type 3c may include:

• Hypoglycaemia (low blood sugar)
• Stomach pain
• Unintended weight loss
• Feeling tired
• Flatulence (excessive wind)
• Steatorrhoea (fatty stools)
• Diarrhoea

These may well be accompanied by the general symptoms of hyperglycaemia caused by diabetes, which include:

• Going to the toilet a lot, especially at night

• Being really thirsty
• Genital itching or thrush
• Cuts and wounds taking longer to heal
• Blurred eyesight
• Increased hunger

The current general lack of awareness among the general public and some healthcare professionals of Type 3c means that misdiagnosis as Type 2 is a strong possibility, since they share diagnostic features (Diabetes UK).  

Managing and Treating Type 3c Diabetes

Like other forms of diabetes, there is no known “cure” for Type 3c, since most damage to the pancreas is currently irreversible, and therapeutic approaches tend to focus on management of the symptoms, particularly maintenance of HbA1c less than 48 mmol/l or 6.5%. Managing type 3c diabetes can be difficult. Drugs prescribed for it include insulin injections and metformin, which treats insulin-resistance and helps the small amounts of insulin still being produced by the pancreas to work more effectively.  Often, those with type 3c diabetes have to move onto insulin therapy at an earlier stage than those with Type 2.  There isn’t yet a definitive treatment regimen that is right for everyone. This is partly because the degree of damage to the pancreas varies so widely, and its function is thus impacted in different ways in different people.  

Close cooperation between a patient and their diabetes healthcare team is vital, with regular monitoring for diabetes complications such as eyesight, kidney, and foot problems, and slow to heal wounds or infections.  Other good advice for those with Type 3c can be found here.

Aside from diabetes symptoms, the difficulty digesting food caused by the exocrine insufficiency might be managed by changes in diet or medications aimed at improving digestion, such as an oral pancreatic enzyme replacement called pancreatic enzyme replacement therapy (PERT) or Pancreatin.   Effective treatment and management of the underlying pancreatic disease is a key part of managing Type 3c diabetes. Such treatment could include anti-inflammatory drugs such as steroids, quitting smoking and not drinking alcohol, and eating a diet rich in soluble fibre and vitamin D, and low in fat.