## 3 Open Loop Administration of an Insulin
### Subcutaneous Versus Inhaled Insulin  
Inhaled insulin has been proven way more effective and reliable in the T1 DM and T2 DM. Infusion of regular insulin through lungs by inhalation has shown insulin absorption and lowering of the BG [55]. As shown in Figure 5, the maximum insulin concentration is more rapid in case of inhaled insulin as compared to the subcutaneous (SC) injection [56]. In subcutaneous insulin (SCI), the short-acting insulin driven by a mechanical force and delivered via a needle or soft cannula under the skin is undertaken on a continuous and constant basis [57]. Although SCI is expensive, but it provides greater flexibility for the individuals having diabetes in managing their condition, and it allows more precise insulin dosing than multiple daily injections (MDI) [58]. According to systematic reviews, potential benefits of SCI include improved glycaemic control, reduction in the hypoglycaemia unawareness, lower insulin doses, high absorption, and a lower frequency of severe hypoglycaemia [59; 60; 61]. Due to the development of sensor augmented insulin therapy with or without suspend functions [62; 63], the T1 DM control and quality of life for patients have significantly enhanced [64; 65]. Moreover, SCI is most successful  
Figure 4: Comparison of delayed and standard insulin delivery with the meal (adopted from [38]).  
in individuals motivated to manage their condition and supported by a multidisciplinary team with expertise in the delivery of SCI [66]. In contrast, inhalable insulin is a powdered form of insulin, delivered with an inhaler into the lungs where it is absorbed [67].  
In general, inhaled insulins absorb more rapidly than SCI insulin, with faster peak concentration in serum and more rapid metabolism [68]. Sanofi-Aventis developed the first commercial inhaled insulin product (Exubera), which was approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2006 and marketed by the Pfizer [69]. Although Exubera offered the advantage of painless insulin administration by the pulmonary route of administration, its pharmacokinetics (PK) and pharmacodynamics (PD) (i.e., PK/PD) characteristics were similar to the SCI injected rapid-acting insulin analogs (aspart, glulisine, and lispro) and, thus, offered no additional clinical benefit in postprandial glycemic control [70]. Furthermore, the inhaler device was large and the handling procedure for insulin administration was cumbersome [71; 72]. Afrezza, an inhaled insulin with ultra-rapid PK/PD properties that enable improved postprandial glycemic control in adults with T1 DM or T2 DM has been suggested as a promising tool [73]. Improvements in the PK/PD characteristics of today's SC insulins provide more physiological coverage of basal and prandi insulin requirements than inhaled insulin, that why SC is most widely used. Furthermore, the treatment with SC offers a safe and efficacious option for managing diabetes in patients with T1 DM and T2 DM [74]. The inhaled insulin delivery may cause safety issues in lungs. We refer interested readers for more detailed understanding about both these two insulin methods to the latest findings in recent studies [75; 76; 77; 78; 79; 80]. Pharmacokinetics deals with the absorption and distribution process of the insulin in a human body. Insulin is absorbed into the blood stream directly [81]. The rate of the absorption truly depends on the state of insulin, volume of the injection, and rate of the blood flow. It has been reported in literature that the absorption rate decreases with an increase in the concentration and the volume. Existing studies demonstrated that inhaled insulin can absorb faster in the human body [82]. Pharmacodynamics deals with effect of insulin on the human body. It is basically called the euglycaemic clamp study, and glucose infusion rate is used to represent the pharmacodynamics of an insulin [83].