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Early initiation of insulin in people living with type 2 diabetes

Dec 05, 2018

Type 2 diabetes (T2DM) is a progressive disease characterized by insulin resistance (IR) and beta cell dysfunction. At diagnosis, 50% of beta cells are already lost. This  continues as the disease progresses [1-2]. Preservation of residual beta cells is an important target [3]. Usually, T2DM treatment starts with lifestyle improvements, followed by metformin. If the patient is unable to achieve their glycemic target, traditionally a number of other agents are prescribed sequentially, including secretagogues. These additions can lead to further deterioration of beta cell numbers and functionality, provoking the development of complications. While most people living with T2DM will need insulin later in life, early initiation will reduce not only the complication burden [4], but may prevent the need for dose escalation, hence reduce treatment costs [5].

Insulin physiology:
Healthy individuals maintain a fasting blood glucose in the range of 3.5-7.0mmol/L by insulin secretion irrespective of nutritional intake, physical activity etc. Fifty-percent of insulin is secreted in the basal period, and the rest is secreted post-prandial. The first phase of the latter starts within two minutes of nutritional intake and continues for 10-15 minutes followed by a second phase until normoglycemia is achieved. Insulin activates insulin receptors causing multiple signaling pathways resulting in an influx of glucose into the cells for further disposal.

Insulin pathophysiology in T2DM:
A majority of T2DM starts with IR [6] followed by compensatory hyperinsulinemia [7] resulting in a gradual loss of beta cell mass and function [8] and onset of T2DM.

Why do people living with T2DM need insulin?
A myriad of factors are involved in T2DM. Medications, including secretagogues, target different factors.  Their continuation can exacerbate the decline of beta cell mass and their function. Since IR and beta cell dysfunction/loss play an important role, hypoinsulinemia should be corrected at the earliest opportunity. First phase insulin secretion is lost at diagnosis, followed by decreasing maximal capacity of insulin secretion. Lastly, defects in basal cell secretion lead to complete failure of beta cells thus requiring insulin treatment [9].

When do people living with T2DM need insulin?
Hyperglycemia and IR are associated with multiple vascular complications [10-11]. Apart from situations when insulin is prescribed immediately, treatment of T2DM usually starts with metformin orally. If the HbA1C response is not adequate in three months, a second non-secretagogue agent is prescribed, however a third oral agent is inferior to the addition of insulin [12-13]. According to the ORIGIN trial, basal insulin is a good choice after metformin, leading to better vascular outcomes.

The patient’s adherence to insulin in the real world:
“Psychological insulin resistance,” and “clinical inertia among healthcare providers and patients’ opposition to insulin therapy” are the two major obstacles to timely initiation and intensification of insulin therapy. Individuals with diabetes sometimes feel that insulin is the ‘beginning of the end’. Since moderate hyperglycemia is symptomless, patients do not realize they need exogenous insulin [14].

Early initiation of insulin in T2DM leads to the preservation of residual beta cells. Such practice reduces vascular complications, insulin dose escalation, treatment costs, and can avoid adverse effects of available non-insulin agents with better prognosis.

Please consider the following questions:

From your clinical experience (for health care professionals):

1.    Do you think that early initiation of insulin will lead to better prognosis of people living with T2DM? If yes, why? If not, why?
2.    Do you use insulin as the second line agent after metformin? If yes, why? If not, why?
3.    Traditionally after metformin, most clinicians prescribe a second non-insulin agent. For third line treatment, which agent do you prefer?
4.    When the question arises, secretagogue or insulin, which one would you prefer?
5.    What kind of barriers do you face in clinical practice during the initiation and continuation of insulin?

Thinking of your own personal experience (for people living with T2DM ):

1.    Could you please tell a little why insulin is beneficial in people living with T2DM ?
2.    Insulin is the beginning of the end. What is your perspective?
3.    Your doctor advises you to start insulin. Would you decline?

Recommended links for more information:


Reference reading:

  1. Diabetes mellitus in the elderly: insulin resistance and/or impaired insulin secretion? Scheen AJ. Diabetes Metab. 2005 Dec; 31 Spec No 2():5S27-5S34.
  2. U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes. 1995 Nov; 44(11):1249-58.
  3. beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Porte D Jr, Kahn SE. Diabetes. 2001 Feb; 50 Suppl 1():S160-3.
  4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
  5. 26th American Association of Clinical Endocrinologists (AACE) Annual Scientific Sessions & Clinical Congress, May 3-7, in Austin, Texas.
  6. Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014;6(1). pii: a009191.
  7. Kido Y, Burks DJ, Withers D, et al. Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. J Clin Invest. 2000;105(2):199-205.
  8. P. Marchetti, M. Bugliani, R. Lupi, L.Marselli, M. Masini, U. Boggi, et al.The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients Diabetologia, 50 (12) (2007), pp. 2486-2494. U.K. Prospective Diabetes Study Group.
  9. U.K. Prospective Diabetes Study 16: Overview of 6 years’ therapy of type II diabetes : a progressive disease. Diabetes 1995 ; 44 : 1249-58.
  10. Lteif A, Vaishnava P, Baron AD, Mather KJ. Endothelin limits insulin action in obese/insulin-resistant humans. Diabetes. 2007;56(3):728–734.
  11. Poor glycemic control in diabetes and the risk of incident chronic kidney disease even in the absence of albuminuria and retinopathy: Atherosclerosis Risk in Communities (ARIC) Study. Bash LD, Selvin E, Steffes M, Coresh J, Astor BC  Arch Intern Med. 2008;168(22):2440.
  12. Gavin JR III. Practical approaches to insulin therapy. Diabetes Educ. 2007;33:66S-73S.
  13. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care. 2006;29:1963-1972
  14. Korytkowski M. When oral agents fail: Practical barriers to starting insulin. Int J Obes Relat Metab Disord. 2002;26:518-524.

Information about the discussion leader

Dr. Gauranga Chandra Dhar MD is a family physician from Bangladesh, graduated from Rostov State Medical Institute, Russia in 1983. He is an assistant professor of the Bangladesh Institute of Family Medicine and Research, University of Science and Technology of Chittagong (USTC), Bangladesh. He is involved in teaching diabetes and other cardiometabolic diseases in postgraduate medical courses since 2011. He has 30-yrs of extensive experience in the management of cardiometabolic diseases including diabetes. He has a number of research papers presented in both national and international conferences on diabetes and related topics.