Those of us living with type 1 diabetes (T1D) hear a lot about the destruction of insulin-producing beta cells — but rarely does anyone discuss the other hormones that are altered due to the autoimmune attack on our pancreatic islet cells. Here, we’ll explore these key hormones, thanks to findings by researchers, including those by Claresa Levetan, MD.

 

Inside the Islets 

The lion’s share of the pancreas is made up of acinar cells, which produce digestive enzymes and are part of the exocrine system. A much smaller proportion of the pancreas makes up the endocrine cells, also known as the Islets of Langerhans (islets).

Beta cells are only one of the five cells in the islets (clusters of pancreatic cells), each containing up to a few thousand endocrine cells. When an autoimmune attack occurs on beta cells, it results in islet dysfunction, too. Unfortunately, the terms beta cells and islets are used interchangeably, in error.  

Pancreatic islets contain alpha, beta, gamma, delta, and epsilon cells. These five cells communicate constantly within the islets to secrete six hormones that, when working properly, maintain blood glucose levels within a very narrow range. 

 

Islets cells and their roles 

Cell  Hormone(s) produced  Role 
Alpha  Glucagon  This hormone raises the concentration of glucose in the bloodstream.  In a healthy islet, glucagon is suppressed after a meal and rises immediately when glucose is dropping, which is why it is given for severe hypoglycemia. 
Beta  Insulin 

  

 In a healthy islet, insulin is secreted within 60 seconds of a carbohydrate being digested, in the exact amount required to maintain healthy glucose levels. Insulin stimulates glucose uptake by the liver, skeletal muscle, and adipose tissue. 
Amylin  This hormone is co-secreted with insulin in equal concentrations. It has several functions, including binding to brain receptors to stimulate feelings of fullness when eating. Amylin also suppresses glucagon release, helping to prevent hyperglycemia after eating. In T1D and T2D, glucagon is not restrained after meals. 
Gamma   Pancreatic polypeptide (PP)  Insulin stimulates the release of PP, an important regulator of glycogen storage in the liver. PP has been shown to enhance insulin sensitivity and reduce insulin requirements in people with T1D on pumps. 
Delta  Somatostatin   Somatostatin inhibits the secretion of glucagon and insulin to stabilize glucose. 
Epsilon  Ghrelin  This hormone stimulates appetite, increases fat storage, and releases growth hormone from the pituitary gland. Abnormal ghrelin secretion has been shown in new-onset T1D. 

 

The Non-Compliant Pancreas 

Postmortem evaluations on people with T1D and T2D both show a loss in the number of beta cells and a reduction in the number of islets and overall islet mass. Due to human physiology, insulin alone cannot restore islet functionality to achieve “euglycemia,” or normal glucose levels.

Once the beta cells are depleted and no longer functional, the communication within the islets goes awry. Given only insulin, people with T1D experience first-hand, that when acting as their own endocrine pancreas, maintaining blood glucose levels “in range” is a time-consuming and challenging job.

People living with T1D can do everything right and still have high and low blood sugars. This can not only be frustrating but also lead to labels such as “poorly controlled” by the medical field —implying it’s their fault. Doctors and society are quick to blame the patient, but as Dr. Levetan says: “It’s the pancreas that is non-compliant, not the patient.”  

 

Consider that, in those living without diabetes: 

  • The majority of blood glucose levels are in the 60 to 100 mg/dL range, and  
  • Post-prandial (after-meal) blood glucose levels are generally <140mg/dL 

 

Given the tools currently available to them, relatively few people with T1D are able to meet the criteria above. Moreover, when A1C (a 3-month average of blood glucose) is elevated, there’s an increased risk for coronary artery disease and other long-term health complications.

With only insulin, diet, and exercise—and even with new, automated insulin delivery (AID) systems—people living with T1D cannot be expected to mimic the intricate communication of the five islet cells 24 hours a day. This is an impossible task.

Imagine running today’s automobile on fuel and engine oil alone. No coolant, no transmission fluid, and no brake fluid. How well would that car run, and for how long? That’s akin to what is expected of many people with T1D: to run the pancreas well on fuel (food) and engine oil (insulin) alone.

That said, current standards of care for the management of T1D do not dictate the use of additional hormonal replacement. 

 

Our Options 

Over 100 years ago, in 1921, Dr. Frederick Banting and his team isolated insulin for therapeutic use, with several options now available. Eighty-four years later, in 2005, Symlin (pramlintide) was FDA-approved for T1D care to mimic amylin. No other products on the U.S. market are FDA-approved to help mimic other islet hormones in people living with T1D. Unfortunately, Symlin’s side effects, its required multiple daily dosing, and general instability have prevented it from becoming particularly popular.

While innovative diabetes devices have made the hour-by-hour management of T1D more bearable, they’re still limited. 

T2D patients, however, have several options including biguanides (i.e., metformin), incretin mimetics (i.e., GLP-1 receptor agonists), and SGLT2 inhibitors. Some endocrinologists prescribe these therapies off-label for those with T1D — under informed consent — and are often successful in helping with glucose management. However, they may not be covered by insurance because they’re not FDA approved as a T1D treatment. This can make GLP-1s, in particular, cost-prohibitive.  

Recent U.S. studies of GLP-1 use in T1D management show great promise. Two studies indicated that there were no major trends in negative outcomes among people with T1D who received GLP-1 with insulin therapy: A1C, body weight, and insulin doses were more effectively reduced than with insulin alone. While there was an increased risk of hypoglycemia, the authors noted that hyperglycemia with ketosis was rare and without ketoacidosis.  

 

 

GLP-1 Research Update by Dr. Natter

At the ADA’s 84th Scientific Sessions, the T1D Exchange Quality Improvement Collaborative (T1DX-QI) presented research on GLP-1 use in people with T1D. As a practicing endocrinologist and person with T1D, I was particularly interested in the following studies on GLP-1 use.

 

 

These studies uncovered that adult endocrine clinics were prescribing GLP-1s more frequently to people living with T1D as an adjunctive therapy. Within the centers studied, 50% of pediatric and 75% of adult centers believe GLP-1 therapies have a role in T1D management as an additional treatment.

Results suggest modest improvements in A1C results (over 6 to 12 months), with no significant change in BMI or DKA events. More research is needed, with larger sample sizes, to learn about the safety, proper dosing, and long-term effects of GLP-1s in T1D.

 

 

Bottom Line

Although we’d prefer a cure, people with T1D may soon have more therapies available to better manage blood glucose directly. In the meantime, as you balance your insulin, food choices, and exercise, channel Dr. Levetan’s wisdom: “Your pancreas is non-compliant, not you.”

 

 •••••

Sources 

  • Levetan, Claresa. (2010), Distinctions between islet neogenesis and β-cell replication: Implications for reversal of Type 1 and 2 diabetes. Journal of Diabetes, 2: 76-84.   
  • Levetan, Claresa & Pierce, Susan. (2012). Distinctions Between the Islets of Mice and Men: Implications for New Therapies for Type 1 and 2 Diabetes. Endocrine practice: official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 19. 1-36.  
  • Levetan, Claresa. (2022), Frederick Banting’s observations leading to the potential for islet neogenesis without transplantation. Journal of diabetes. 14, 2: 104-110.  
  • Rabiee A, Galiatsatos P, Salas-Carrillo R, et al. (2011), Pancreatic polypeptide administration enhances insulin sensitivity and reduces the insulin requirement of patients on insulin pump therapy. J Diabetes Sci Technol. 5:1521-1528. 
  • Holdstock C, Ludvigsson J, Karlsson FA. (2004), Abnormal ghrelin secretion in new-onset childhood Type 1 diabetes. Diabetologia. 47: 150–1.
  • Diabetes Control and Complications Trial (DCCT): results of feasibility study. The DCCT Research Group. Diabetes Care. 1987 Jan-Feb;10(1):1-19. doi: 10.2337/diacare.10.1.1. PMID: 2882967.
  • Dejgaard, TF, von Scholten, BJ, Christiansen, E, et al. (2021), Efficacy and safety of liraglutide in type 1 diabetes by baseline characteristics in the ADJUNCT ONE and ADJUNCT TWO randomized controlled trials. Diabetes Obes Metab. 23( 12): 2752- 2762.