Read Time: 3 mins

What Breathing Insulin Means for Diabetes Treatment

Copy Link
Published Online: Jun 6th 2011 US Endocrinology, 2006;(2): DOI:
Authors: Marc Rendell
Quick Links:
Article Information

Type 1 diabetes is a disease of severe deficiency of endogenously secreted insulin. When introduced in the late 1920s, injected insulin treatment proved to be a lifesaving treatment for type 1 patients. The primary abnormality in type 2 diabetes is a relative deficiency of insulin secretory capacity resulting in insufficient response to tissue insulin resistance. Normalization of blood glucose levels is the goal of diabetes treatment.Yet, a large proportion of patients with diabetes fail to meet recommended glycemic goals. Two-thirds of patients (67%) in one survey conducted by the American College of Clinical Endocrinologists failed to meet the target goal of 6.5% glycosylated hemoglobin (HbA1c).1


Although there are many oral hypoglycemic agents to stimulate insulin secretion, reduce insulin resistance, and slow glucose absorption, even combinations of multiple agents often fail to achieve normal HbA1c.2 Perhaps, more important, multiple oral agents (OAs) do not sufficiently reduce postprandial hyperglycemia.3,4 The most effective means of lowering blood sugar is externally administered insulin, particularly in patients with very high glucose levels.5 Due to degradation and poor absorption by the digestive system, insulin has historically been delivered

Although there are many oral hypoglycemic agents to stimulate insulin secretion, reduce insulin resistance, and slow glucose absorption, even combinations of multiple agents often fail to achieve normal HbA1c.2 Perhaps, more important, multiple oral agents (OAs) do not sufficiently reduce postprandial hyperglycemia.3,4 The most effective means of lowering blood sugar is externally administered insulin, particularly in patients with very high glucose levels.5 Due to degradation and poor absorption by the digestive system, insulin has historically been delivered subcutaneously (SC) by injection. Although injections with a small needle are almost painless, puncture of the skin elicits significant psychological resistance in the majority of patients.The reluctance of patients to accept insulin injections also stems from additional concerns including possible weight gain, risk of hypoglycemia, embarrassment at being observed injecting oneself, and the perception of having failed to control the disease.6,7 Physicians also may be resistant to the use of insulin due to concern about the potential side effects (i.e., weight gain, hypoglycemia), as well as the time required to educate patients about proper insulin injection techniques.6–9

Alternative Insulin Delivery
Due to negative feelings regarding injected insulin, there have been many attempts to develop alternative methods of delivery.10,11 Jet injectors have been used for many years, but reproducibility of dosage has been a concern.12 Furthermore, the discomfort with the use of a jet injector may be greater than caused by a needle stick. Topical application with transdermal absorption has been ineffective. Efforts to enhance absorption with carrier substances, ultrasound, or iontophoresis have not yet proven practical.13–16 Intranasal administration of small peptides like oxytocin, desamido desarginine vasopressin and calcitonin is effective, but bioavailability of nasally administered insulin has proven erratic.17–24 Furthermore, nasal irritation has plagued this approach. Insulin bioavailability by intestinal absorption is limited due to rapid degradation by the digestive system and poor transit of the molecule across the intestinal mucosa.25 A buccal system delivering a liquid aerosol formulation of insulin via a metered dose inhaler (Oralin) has been developed by Generex Biotechnology (Toronto, Canada).26,27 The buccal insulin preparation is a human recombinant insulin with added enhancers, stabilizers, and a non-chlorofluorocarbon (CFC) propellant.To date, however, studies have been limited. Pulmonary Insulin
The most successful alternative route of insulin delivery has been pulmonary. The lung alveoli offer a large surface area with high permeability. Absorption of insulin is optimized by the delivery of a lyophilized powder with a particle size of 1–3 μm in diameter.28,29

There are several inhaled insulins in various stages of development. The most extensively studied inhaled insulin resulted from a joint effort by Nextar and Pfizer. It is a dry powder formulation of human insulin, packaged in foil blisters for long-term stability, dispensed by an insulin inhaler device that punctures the blisters and disperses the powder to a holding chamber to improve the effectiveness and reproducibility of inhalation.30 Extensive studies over the past decade culminated in the recent approval of this system by the US Food and Drug Administration (FDA) under the brand name Exubera.31,32 Other inhaled insulins in the approval chain include the Lilly Alkermes system and Technosphere insulin. The Lilly Alkermes product is also a dry powder formulation with a much smaller inhaler than the Nextar device.33 Technosphere insulin, developed by the Mannkind Corporation, also has a convenient inhaler and a rapid onset of action with shorter duration than the other inhaled insulins.34

Pharmacokinetics of Inhaled Insulin
Exubera inhaled insulin has a faster onset of action than both regular human insulin and insulin lispro, as indicated by shorter time to early half-maximal effect (32 versus 48 and 41 minutes, respectively), with time to maximal effect comparable between inhaled insulin and insulin lispro (143 versus 137 minutes) but shorter than regular human insulin (193 minutes; p<0.01).35 The duration of action (387 minutes) is comparable to regular human insulin (415 minutes) but longer than insulin lispro (313 minutes; p<0.01). Exubera is poorly absorbed; the relative bioavailability is only about 9% over a 10-hour observation period.35

The low bioavailability of inhaled insulin does not lead to variable serum insulin levels; inhaled insulin has proven just as effective as SC administered insulin in controlling glucose levels in both type 1 and type 2 diabetes.36–38 In fact, in several studies, inhaled insulin has proven as or more effective in combination with longacting insulin than SC regular insulin in reduction of HbA1c, fasting and/or postprandial glucose or both.39–41 Addition of long-acting basal insulin to an oral hypoglycemic regimen is effective in substantially lowering HbA1c. 42 Similarly, the addition of pre-meal insulin inhalations is effective in lowering glucose levels in patients poorly controlled on oral hypoglycemics.43 Mean HbA1c concentration in oral hypoglycemic treated patients was reduced by about 2% in the group receiving Exubera plus oral agents, compared with only 0.1% in the group receiving OAs alone (p<0.001), and there was a significantly greater reduction in fasting plasma glucose (FPG) in the inhaled insulin groups as well. Safety of Inhaled Insulin
There are several potential safety concerns with the use of inhaled insulin. Naturally, the greatest risk is that the large amount of protein deposited in the lungs will cause long-term pulmonary damage.The protein is immunogenic as evidenced by the development of insulin antibodies in treated patients.The development of antibodies is presumably related to changes in the tertiary structure of the human insulin molecule.The production of insulin antibodies seems to plateau by 12 months of therapy, and appears to reverse after discontinuation of inhaled insulin.44–45 No correlation has been observed between insulin antibody concentrations and HbA1c concentrations, FPG concentrations, postprandial plasma glucose (PPG) concentrations, the incidence of hypoglycemia, insulin dose or serum concentration, or the incidence of allergic and/or respiratory adverse events.44–46

With long-term use, there are small reductions in both forced expiratory volume (FEV) and diffusion capacity. These changes occur early and do not appear to progress.36–40 As might be expected, coughing is a side effect of inhalation of the dry powder, occurring in 20–30% of patients receiving Exubera. Most patients in reported clinical trials have entered the studies with normal lung function, so it is not clear whether inhalation of insulin may be more detrimental to patients with pre-existing lung disease. Smoking obviously damages the lungs and increases the permeability of the alveolar–capillary barrier.47 Inhaled insulin dose requirements are lower in smokers.48 Changes in inhaled insulin absorption are partially reversible after smoking cessation.48 Smokers were excluded from the Exubera research program, so inhaled insulin is not indicated in these patients.

Overall, the incidence and severity of hypoglycemia with Exubera is similar to that seen with SC regular insulin.36–40 There are, as yet, no head to head studies directly comparing the incidence of hypoglycemia with Exubera to that with shorter acting analog insulins. Patients Prefer to Breathe Their Insulin
Inhaled insulin does not exhibit major clinical differences from injected insulin in glucose lowering effect.However, the key advantage of inhaled insulin therapy is in patient preference for the pulmonary route. In several studies, patients receiving inhaled insulin elected to continue the treatment long term while patients on injections switched to inhaled insulin when given the opportunity.49 The availability of inhalation as an option increases the willingness of patients to accept insulin therapy. In a survey of patient preferences of over 700 type 2 diabetic patients with poorly controlled diabetes, Freemantle et al found that 43% of patients offered the inhalation route would accept insulin treatment in contrast to only 15% who had injections as the sole option.50 In a randomized crossover study using a number of validated survey instruments, 80% of patients with type 1 diabetes preferred Lilly-Alkermes inhaled insulin rather than SC insulin.51 Insulin has greater potential to lower HbA1c than OAs.Therefore, patient willingness to accept inhaled insulin represents a substantial opportunity to normalize glucose levels in diabetic patients not well controlled on oral hypoglycemics.

Exogenous insulin administration is the most effective technique to normalize blood glucose levels. Patients are reluctant to accept insulin injections. Insulin is absorbed by the lungs with favorable kinetics. In many studies, inhaled insulin has proven to be as effective as injected insulin in controlling blood glucose. Studies to date suggest that inhaled insulin does not cause pulmonary damage in patients with normal lung function.Although inhaled insulin is immunogenic, there is no evidence that antibody development has deleterious effects. Hypoglycemic reactions do not appear to occur more frequently with inhaled insulin than with SC regular insulin. The primary advantage of pulmonary administration of insulin is strong patient preference over injected insulin. As a result of the favorable perception of inhaled insulin, patients are more receptive to the use of insulin to control their diabetes.


  1. American Association of Clinical Endocrinologists, “State of diabetes in America”, available at: releases/index.php?r=20050518_11. Accessed October 12, 2005.
  2. Bell DS,Ovalle F,“Long-term glycaemic efficacy and weight changes associated with thiazolidinediones when added at an advanced stage of type 2 diabetes”, Diabetes Obes Metab (2006);8: pp. 110–115.
  3. Rendell M,“Post-prandial hyperglycemia:Why do we care about it? What should we do?”, Drug Develop Res (2006);67: pp. 1–5
  4. Rendell MS, Jovanovic L,“Targeting postprandial hyperglycemia”, Metabolism (2006);55: pp. 1263–1281.
  5. Rosenstock J, Sugimoto D, Strange P et al.,”Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus metformin in insulin-naive patients”, Diabetes Care (2006);29: pp. 554–559.
  6. Peyrot M, Rubin RR, Lauritzen T et al.,“Resistance to insulin therapy among patients and providers: results of the cross-national Diabetes Attitudes,Wishes, and Needs (DAWN) study”, Diabetes Care (2005);28: pp. 2673–2679.
  7. Polonsky WH, Fisher L, Guzman S,Villa-Caballero L, Edelman SV, “Psychological insulin resistance in patients with type 2 diabetes: the scope of the problem”, Diabetes Care (2005);28: pp. 2543–2545.
  8. Snoek FJ, “Breaking the barriers to optimal glycaemic control—what physicians need to know from patients’ perspectives”, Int Clin Pract Suppl (2002); pp. 80–84.
  9. Miller CD, Phillips LS, Ziemer DC et al., “Hypoglycemia in patients with type 2 diabetes mellitus”, Arch Intern Med (2001);161: pp. 1653–1659.
  10. Cefalu WT, “Concept, strategies, and feasibility of noninvasive insulin delivery”, Diabetes Care (2004);27: pp. 239–246.
  11. Saudek CD,“Novel forms of insulin delivery”, Endocrinol Metab Clin North Am (1997);266: 599B610.
  12. American Diabetes Association,“Insulin administration (Position Statement)”, Diabetes Care (2002); 25(Suppl 1): S112BS115.
  13. Heinemann L, Pfutzner A, Heise T, “Alternative routes of administration as an approach to improve insulin therapy: update on dermal, oral, nasal and pulmonary insulin delivery”, Curr Pharm Des (2001);7: 1327B1351.
  14. Langkjaer L, Brange J, Grodsky GM, Guy RH,“Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment”, J Control Release (1998);51: 47B56.
  15. Kanikkannan N, Singh J, Ramarao P, “Transdermal iontophoretic delivery of bovine insulin and monomeric human insulin analogue”, J Control Release (1999);59: p. 99B105.
  16. Mitragotri S, Blankschtein D, Langer R,“Ultrasound-mediated transdermal protein delivery”, Science (1995);269: 850B853.
  17. Jacobs MA, Schreuder RH, Jap-A-Joe K et al.,“The pharmacodynamics and activity of intranasal administered insulin in healthy male volunteers”, Diabetes (1993);42: 1649B1655.
  18. Frauman AG, Jerums G, Louis WJ, “Effects of intranasal insulin in nonobese type II diabetics”, Diabetes Res Clin Pract (1987); 3: 197B202.
  19. Gordon GS, Moses AC, Silver RD, Flier JS, Carey MC, “Nasal absorption of insulin: enhancement by hydrophobic bile salts”, Proc Natl Acad Sci U S A (1985);82: 7419B7423.
  20. Salzman R, Manson JE, Griffing GT et al., “Intranasal aerosolized insulin: mixed meal studies and long-term use in type 1 diabetes”, N Engl J Med (1985);312: 1078B1084.
  21. Coates PA, Ismail IS, Luzio SD et al.,“Intranasal insulin: the effects of three dose regimens on postprandial glycaemic profiles in type II diabetic subjects”, Diabet Med (1995);12: 235B239.
  22. Hilsted J, Madsbad S, Hvidberg A et al.,“Intranasal insulin therapy: the clinical realities”, Diabetologia (1995);38: 680B684.
  23. Lalej-Bennis D, Boillot J, Bardin C et al.,“Efficacy and tolerance of intranasal insulin administered during 4 months in severely hyperglycaemic type 2 diabetic patients with oral drug failure: a cross-over study”, Diabet Med (2001);18: 614B618.
  24. Lalej-Bennis D, Boillot J, Bardin C et al.,“Six month administration of gelified intranasal insulin in 16 type 1 diabetic patients under multiple injections: efficacy vs subcutaneous injections and local tolerance”, Diabetes Metab (2001);27: 372B377.
  25. Still JG,“Development of oral insulin: progress and current status”, Diabetes Metab Res Rev (2002);18 (Suppl 1): S29BS37.
  26. Owens DR, Zinman B, Bolli G, “Alternative routes of insulin delivery”, Diabet Med (2003);20: pp. 886–898.
  27. Arbit E,“The physiological rationale for oral insulin administration”, Diabetes Technol Ther (2004);6: pp. 510–517.
  28. Patton JS,“Mechanisms of macromolecule absorption by the lungs”, Adv Drug Deliv Rev (1996);19: pp. 3–36.
  29. Patton JS, “Deep-lung delivery of therapeutic proteins”, Chemtech (1997);27: pp. 34–38.
  30. Barnett AH,“Exubera inhaled insulin: a review”, Int J Clin Pract (2004);58: pp. 394–401.
  31. “First inhaled insulin product approved”, FDA Consum (2006);40: pp. 28–29.
  32. Lenzer J, “Inhaled insulin is approved in Europe and United States”, BMJ (2006);11;332(7537): p. 321.
  33. Rave K, Nosek L, De La Peña A et al., “Dose response and dose equivalency of human insulin inhalation powder (HIIP) using the Lilly/Alkermes inhaled insulin system compared to subcutaneous (SC) insulin lispro”, Diabetes (2005);54: p.A89, abstract 360-OR.
  34. Boss AH, Grant ML, Cheatham WW,“Mimicry of the early phase insulin response in humans with rapidly available inhaled insulin accelerates postprandial glucose disposal compared to slower bioavailable insulin”, Diabetes (2005);54: p.A333, abstract 1373-P.
  35. Rave K, Bott S, Heinemann L et al., “Time-action profile of inhaled insulin in comparison with subcutaneously injected insulin lispro and regular human insulin”, Diabetes Care (2005);28: pp. 1077–1082.
  36. Defronzo RA, Bergenstal RM, Cefalu WT et al.,“Efficacy of inhaled insulin in patients with type 2 diabetes not controlled with diet and exercise: a 12-week, randomized, comparative trial”, Diabetes Care (2005);28: pp. 1922–1928.
  37. Hollander PA, Blonde L, Rowe R et al.,“Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes: results of a 6-month, randomized, comparative trial”, Diabetes Care (2004);27: pp. 2356–2362.
  38. Quattrin T, Belanger A, Bohannon NJ, Schwartz SL, “Efficacy and safety of inhaled insulin (Exubera) compared with subcutaneous insulin therapy in patients with type 1 diabetes: results of a 6-month, randomized, comparative trial”, Diabetes Care (2004);27: pp. 2622–2627.
  39. Skyler JS,Weinstock RS, Raskin P et al., “Use of inhaled insulin in a basal/bolus insulin regimen in type 1 diabetic subjects: a 6-month, randomized, comparative trial”, Diabetes Care (2005);28: pp. 1630–1635.
  40. Cefalu WT, Skyler JS, Kourides IA et al, “Inhaled human insulin treatment in patients with type 2 diabetes mellitus”, Ann Intern Med (2001);134: pp. 203–207.
  41. Weiss SR, Cheng S-L, Kourides IA, Gelfand RA, Landschulz WH, “Inhaled insulin provides improved glycemic control in patients with type 2 diabetes mellitus inadequately controlled with oral agents: a randomized controlled trial”, Arch Intern Med (2003);163: pp. 2277–2282.
  42. Riddle MC, Rosenstock J, Gerich J, Insulin Glargine 4002 Study Investigators, “The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients”, Diabetes Care (2003);26: pp. 3080–3086.
  43. Rosenstock J, Zinman B, Murphy LJ et al., “Inhaled insulin improves glycemic control when substituted for or added to oral combination therapy in type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2005;143:549-558.
  44. Fineberg SE, Kawabata T, Finco-Kent D, Liu C, Krasner A, “Antibody response to inhaled insulin in patients with type 1 or type 2 diabetes.An analysis of initial phase II and III inhaled insulin (Exubera) trials and a two-year extension trial”, J Clin Endocrinol Metab (2005);90: pp. 3287–3294.
  45. Heise T, Bott S,Tusek C et al., “The Effect of Insulin Antibodies on the Metabolic Action of Inhaled and Subcutaneous Insulin: a prospective randomized pharmacodynamic study”, Diabetes Care (2005);28: pp. 2161–2169.
  46. Teeter JG, Riese RJ,“Dissociation of lung function changes with humoral immunity during inhaled human insulin therapy”,Am J Respir Crit Care Med (2006);173(11): pp. 1194–1200.
  47. Jones JG, Minty BD, Lawler P et al.,“Increased alveolar epithelial permeability in cigarette smokers”, Lancet (1980);1: pp. 66–68.
  48. Sha S, Becker R,Willavise S et al., “The effect of smoking cessation on the absorption of inhaled insulin (Exubera)”, Diabetes (2002);51 (Suppl 1): p.A133, abstract 538.
  49. Rosenstock J, Cappelleri JC, Bolinder B, Gerber RA,“Patient satisfaction and glycemic control after 1 year with inhaled insulin (Exubera) in patients with type 1 or type 2 diabetes”, Diabetes Care (2004);27: pp. 1318–1323.
  50. Freemantle N, Blonde L, Duhot D et al.,“Availability of inhaled insulin promotes greater perceived acceptance of insulin therapy in patients with type 2 diabetes”, Diabetes Care (2005);28: pp. 427–428.
  51. Hayes RP, Muchmore DB, Silverman B,“Drivers of treatment preference for the Lilly/Alkermes inhaled insulin system in patients with type 1 diabetes (T1D)”, Diabetes (2005);54: p.A495, abstract 2055-PO.

Further Resources

Share this Article
Related Content In Diabetes
  • Copied to clipboard!
    accredited arrow-down-editablearrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greenarrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-red tick-whiteticktimetranscriptup-arrowwebinar Sponsored Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72