Glucagon and the Alpha Cell: The Next Frontier in Diabetes Treatment
Much has changed about the way clinicians think about and treat diabetes over the last few decades. A fact due, in large part, to a better understanding of the metabolic defects in type 2 diabetes and heightened awareness of how newer medications address these defects. This, combined with increasingly reliable means to measure hemoglobin A1c (HbA1C) and the development of more effective tactics for motivating patients to adhere to their diabetes regimens, provides clinicians with a significantly improved ability to diagnose and monitor diabetes patients. However, there are still many unanswered questions regarding the most impactful way to treat diabetes. One of the most exciting of which surrounds the influence of glucagon and the alpha cell.
For years, diabetes research and treatment has centered on the beta cell and insulin, resulting in the creation of multiple medications that focus on the lack of insulin from the beta cell or insulin resistance. Only recently have medications (incretin class) been developed that impact the alpha cell and alter glucagon production. This is possible because glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors reduce plasma glucagon concentrations,1 a significant benefit to patients with type 2 diabetes who are plagued by excessively high post-meal blood sugars (even if they have consumed very few carbohydrates). Additionally, in patients where hyperglycemia is present, increased glucose is associated with a rise in glucagon levels. These new treatment options help to decrease glucagon and better control hyperglycemia.
Along with stabilizing post-meal glucagon, these medicines also are blood sugar normalizing medications or euglycemics (drugs that help return the blood sugar to the normal range). The incretin-based medicines are available in two families of medicines: DPP-4 inhibitors and GLP-1 analogs Sitagliptin, saxagliptin, and linagliptin are DPP-4 inhibitors and are taken as pills. Exenatide and liraglutide are GLP-1 analogs and are taken by injection as are albiglutide and dulaglutide.
GLUCAGON
Normally glucagon is released from the alpha cell in response to hypoglycemia or any event that requires extra glucose like exercise. Glucagon stimulates the liver to break down glycogen, activates the conversion of amino acids into glucose (gluconeogenesis), and breaks down stored fat (triglycerides) into fatty acids to use as fuel for cells. Hyperglycemia usually decreases glucagon secretion,2 but there is considerable evidence that aberrant secretion of glucagon from the alpha cell contributes to the metabolic derangements seen in diabetes. What we have seen is that many diabetic patients with hyperglycemia also have elevated blood concentrations of glucagon. Based on clinical experience and research, it is becoming clearer, that an excess of glucagon, rather than an insulin deficiency, may be the primary defect in diabetes and contribute to both type 1 and 2 diabetes.3
In our practice, therapy for our diabetes patients have focused on different metabolic targets, which has helped us to better understand the influence of glucagon on glucose control. Sodium glucose cotransporter-2 (SGLT-2) inhibitors focus on increased glucose loss in the urine and ironically produce an increase in glucagon levels. Combining incretin memetics with SGLT-2 inhibitors reduces this paradoxical increase in glucagon and leads to a reduction in hyperglycemia and HbA1c.
RESEARCH
A recent addition to diabetes treatment, SGLT-2 inhibitors, lowers HbA1c and paradoxically increases glucagon levels. The mechanism for the glucagon increase is not clear but may be related to SGLT-1 inhibition. SGLT1 is the major intestinal glucose transporter, contributing only 10% to renal glucose reabsorption. Intestinal glucose transport influences GLP-1 levels and therefore glucagon levels.
A recent trial of adding DPP-4inhibitor saxagliptin and SGLT-2 inhibitor dapagliflozin to metformin resulted in greater reductions in HbA1c than addition of each component alone. The study also accessed changes in glucagon levels. Glucagon levels were increased with the addition of dapagliflozin to metformin but the increase was eliminated when saxagliptin was added. The SAXA + DAPA combination achieved additional reductions in HbA1c without the increase in insulin seen with SAXA and without the increase in glucagon seen with DAPA.4
Therapeutic options to decrease glucagon now exist with the addition of DPP-4 inhibitors and GLP-1 RAs to SGLT-2 inhibitors. The FDA recently approved the first DPP-4 inhibitors to SGLT-2 inhibitors combination pill, empagliflozin-linagliptin (Glyxambi) to eliminate the increase in glucagon. Drugs combining SGLT-2 and SGLT-1 inhibitors are also in development to decrease the glucagon increase seen with SGLT-2. Drugs that target glucagon receptors and reduce glucagon levels are in phase 1 studies.6
DISCUSSION
The inability of some patients to adhere to lifestyle changes and medication is frustrating for both clinicians and patients. This is secondary to many issues including literacy, numeracy (inability to understand numbers), costs, and diabetes distress. "Diabetes distress" refers to the unique, often hidden, emotional burdens and worries that a patient experiences when they are managing a severe chronic disease like diabetes.7 Many patients have significant other issues both physical and mental that add additional barriers to quality of care. Resources to deal with all of these issues are limited by finances and manpower.
Unfortunately most healthcare dollars are spent on care of diabetes complications once they occur. Many diabetic patients do not have access to adequate primary care and education about self-care of diabetes. Improved reimbursement for primary care, patient education, and advanced training for primary care office teams will aid early recognition and prevention of complications, and reduce the costs and suffering association with diabetes. The time has come to think about defects in both the alpha cell in addition to beta cell defects. Therapeutic options that impacts glucagon may be the next frontier of diabetes treatment.
Edward Shahady, MD, medical director of the Diabetes Master Clinician Program in Fernandina Beach, Florida
References:
1. Drucker DJ, Nauck MA. The incretin system: glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696-1705.
2. Diabetes.co.uk. Glucagon. www.diabetes.co.uk/body/glucagon.html. Accessed
January 2015.
3. Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest. 2012;122(1):4–12.
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5. Zambrowicz B1, Freiman J, Brown PM, Frazier KS et al LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin Pharmacol Ther. 2012 Aug;92(2):158-169.
6. Isis Pharmaceuticals Inc. Metabolic disease. www.isispharm.com/Pipeline/Therapeutic-Areas/Metabolic-Disease.html. Accessed January 2015.
7.Diabetes University DMCP. Diabetes distress learning center. www.diabetesuniversitydmcp.com/diabetes-distress-learning-center.html.
Accessed January 2015.