The quest for a treatment for diabetes has a history as long as the disease itself, dating back to Ebers Papyrus in1500 B.C. The discovery of Insulin on the 30th July 1921 when Frederick Grant Banting and Charles Herbert Best injected 4 c.c. of extract of degenerated pancreas to a dog and the dog’s blood sugar found dropped, was thought to be the ultimate end for the search of treatment of diabetes. However, the presently available insulins can not control the diabetes as good as the insulin of a normal pancreas. The search for a better insulin thus continues.

The available insulin preparations differ with respect to the animal species from which they are obtained, their purity, solubility and the time of onset and duration of action. Insulin is a two-chain polypeptide having 51 amino acids and molecular weight of 6000. The A chain has 21, while B chain has 30 amino acids. The bovine and pork insulins are derived from the respective animals, the human insulins are produced by recombinant DNA technology. There are major differences between amino acid sequence in human, pork and bovine insulins.

Species A chain B chain
______________________________ _______

8th AA 10th AA 30th AA
Human Threonine Isoleucine Threonine

Pork Threonine Isoleucine Alanine

Bovine Alanine Valine Alanine

It is seen that pork insulin is more homologous to human insulin than bovine insulin. With the development of highly purified insulin preparations immunogenecity has been markedly reduced. However, the aim of achieving optimal insulin delivery and thereby reproducing the physiological patterns of insulin secretion is not yet feasible with the presently available insulins. The challenge for the insulin chemist has been to develop two insulin analogues, one type to provide insulin needs in response to meals and another type for a constant delivery of about 1 unit of insulin per hour to meet the needs of the basal state.

Insulin Analogues
The importance of intensive treatment regimens to control blood glucose can not be overemphasized to reduce microvascular and macrovascular complications of diabetes. Ideally, glycaemic control should be as near normal as practicable for each patient(1,2). Pursuit of tighter glycaemic control has encouraged introduction of newer insulins. Insulin analogues represent the latest evolutionary milestone in the more than 80 years history of insulin therapy. Modifications in the structure of insulin using recombinant DNA technology have contributed to understanding the importance of individual and sequences of amino acids in the molecular assembly of insulin, its biological activity and therapeutic properties. The rationale for the design of biosynthetic insulin analogues is, by directed engineering of the primary structure of the protein, to minimize the unwanted properties of insulin while retaining its biological activities. These insulin analogues are attempted to replicate normal insulin secretion both in fasting and fed states following subcutaneous injections. These newer designer insulins allow a customized treatment plan for individualized patients, as individuals suffering from diabetes have different habits and lifestyle needs. With the introduction of newer insulins, a new classification of insulin has been proposed based on speed of onset and duration of action.

Classification of Insulins:

Category Type Onset of action
(mins) Duration of action (mins)
Rapid
Aspart,
Lispro 0 -20 2 -5
Rapid-Intermediate Aspart-Protaminated aspart mixture 10 -20 8 -16
Short Regular 15 -60 4 – 8

Short- Intermediate Regular-Isophane (NPH)
Mixture 15 – 60 8 – 16
Intermediate Isophane (NPH) 60 120 8 -16
Long Lente 120 – 240 16 – 30
Very Long
Glargine 60 120 24

Rapid acting insulin analogues:

Insulin Lispro is a new insulin analogue produced by recombinant technology, where two amino acids near the terminal end of the B chain have been reversed in position. After subcutaneous injection, insulin Lispro quickly dissociates into monomers and absorbed rapidly reaching peak serum values as early as one hour. It can be given 15 minutes before meals in contrast to the regular insulin which should be given preferably half an hour before food. The duration of action lasts for 3 to 4 hours only. This closely mimics the normal physiological insulin production in the body and reduce the incidence of hypoglycaemia in between meals. Insulin Aspart is another short acting insulin analogue which is identical to that of native human insulin except for the substitution of aspartic acid for proline at position B28 of insulin amino acid sequence. This prompts more rapid dissociation from hexamers and dimers leading to rapid release from subcutaneous injection sites.
These new rapid acting insulin analogues, lispro and aspart have quickly established themselves as suited for meal-time injection to boost circulating insulin concentrations to coincide with the period of meal digestion. These insulin analogues are structurally modified for quick absorption into the circulation and have a rapid onset and short duration of action when given just before meals than having to anticipate a meal 15-30 minutes in advance before a meal. These reduce the risk of inter-prandial hypoglycaemia.

Long acting insulin analogues:

These short acting insulins are exciting and control the post prandial hyperglycaemia, however to mimic the physiological insulin secretion, a truly long acting depot insulin to cover the basal requirement in between the foods is also required. This will control blood glucose between meals and during the night. The long acting insulins available now have peaks and valleys, and does not maintain the same level of insulin throughout the 24 hours. Insulin Glargine is a long acting insulin analogue introduced in August 2002, where aspargine is replaced by glycine at amino acid 21 and two arginine residues to the C-terminus of the B chains slowing down its release and reducing its solubility in the blood. The onset of action of insulin Glargine is late, the duration of action is longer lasting for more than 24 hours and there is no pronounced peak and closely matches the basal component of normal insulin release. A lower incidence of hypoglycaemia has been reported with insulin Glargine.

Detemir is another long-acting “basal” insulin analogue, which is linked to a fatty acid, myristic acid. The fatty acid side chain promotes aggregation of detemir in intestinal fluid and delays dissociation and release into the circulation. On entering the blood, the fatty acyl group binds to albumin and a dynamic dissociation from the albumin gives a constant slow rate of release of active monomeric detemir. Studies to-date indicate a predictable effect of detemir on glycaemic control with fewer hypoglycaemias and less weight gain than NPH(10,11).

Biphasic Premixed Insulin formulations:

“Biphasic” premixed formulations of a rapid-acting analogue with protaminated rapid-acting insulin analogue have provided a convenient new means to combine mealtime and basal insulin delivery. These premixed insulin formulations are the combinations of lispro and aspart with isopahane complexes of protamine with lispro and aspart. Biphasic lispro and biphasic aspart are now available and they facilitate mealtime glycaemic control with faster insulin peaks and a flat basal insulin concentrations for inter-prandial glycaemic control.

Conclusion

The newer designer insulins truly mimics the insulin secretion of a normal person, where there are peaks of insulin secretion with every meals with a flat basal secretion to control the blood glucose levels between the meals with little risk of developing hypoglycaemia. Both the fasting and postprandial hyperglycaemias are taken care of by these analogues. With these newer insulins, physicians can design different modalities of treatment for different individual diabetic patients, and diabetic patients may be more liberal with the food timings. These analogues also promise to be the best weapon yet for really tight control of diabetes and thereby preventing or delaying the complications of diabetes mellitus.

References:

1. Cambell IW. Need fir intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol 2000; 7: 625-31
2. Baily CJ, Day C. Antidiabetic drugs. Br J Cardiol 2002; 10: 128-36
1. Owen DR and Luzia SD. Designer Insulins. J. Diab Ass Ind. 1997; 37: 77-80
2. Lee W, Zirman B. From insulin to insulin analogues, progress in the treatment of type 1 diabetes. Diabetes Rev. 1998; 6: 73-88
3. Marks J. Diabetes management in the future: a whiff and a long shot? Clin Diabetes 1998; 16;3

I could now realise that making a film is not that easy as everyone thinks. Even for a small take, they make several repeats which even made a simple spectator like me exhaust up my patience.

Azaleas love an acidic soil. I plant them in decomposed leaf mould and very loose sand with a ratio of 3:1. Prior to plating, the mixture is treated with fungides (systemic) and well dried. After plantation., I use a small dose of nematicide as earthworm tends to make the porous soil clayish. Earthen pots with at least two holes for easy water drainage are used. They are kept in semi shade for which I used a 50% agroshed net.

The nurseries are planted in pots of appropriate sizes. Too big a pot is not good as there is a higher chance of water logging.

Azaleas love water and it needs to be moist all the time but should not be water logged. I water them twice a day (morning and evening).

On the eve of spring, I start feeding with blood meal every 15 days in gap. In between I use foliar spray of micronutrients every week. This cleanses away the leaves as well.

During the growth season, I do a lot of pruning. Although with pruning, I do lose some flowers but it maintains a good bushy structure rather than a long and slender one.

Do’s:
1. Regular exercise (40 minutes daily) at least 3 – 4 hours before bed time
2. Take a hot bath 2 hours before bed time
3. Keep a regular time
i. for bed time
ii. wake up time
iii. do not deviate by > 1 hour
4. Increase exposure to bright light during the day
5. Restrict alcoholic beverage consumption after 7:00 pm (Alcohol can fragment sleep over the 2nd half of sleep)
6. Keep the clock free turned away
7. Review with doctor the medications that could be stimulating/sedating
8. Avoid strenuous exercise after 6 pm
9. Avoid heavy meals/spices in the evening
10. Keep the room dark, quiet, well ventilated and at comfortable temperature throughout night
11. Use bed time ritual reading before light out, it may be helpful if it is relaxing
12. Learn simple relaxing skills if wake up at night
13. Use stress management in day time
14. Set aside worries
15. Make sure mattress is not too soft or too firm and the pillow is of proper height and firmness
16. Use only bed room for sleeping

Don’t’s
1. Avoid naps except for a brief duration (30 minutes) during day (Check with doctors as some disorders can be benefited from short duration naps during day)
2. Avoid spending too much time awake in bed
3. Do not expose to bright light if you have to get up at night
4. Do not smoke after 7 pm
5. Do not eat/drink heavily 3 hours before sleep
6. Do not retire too hungry/too ful
7. Avoid unfamiliar sleep environment
8. Do not work/do other activity in bed room
9. Avoid activities that lead to prolonged arousal

GOOD SLEEP IS A SENSITIVE SIGN OF GOOD HEALTH AS MUCH AS IT IS AN IMPORTANT REQUISITE FOR A HEALTHY LIVING.
“ENJOY YOUR SLEEP”
&
WISH YOU A VERY GOOD NIGHT

Abstract:

Inhaled insulin is a novel therapeutic option among the insulin delivery devices in the management of diabetes mellitus. It may ultimately replace the need for multiple daily subcutaneous injections of insulin. Subcutaneous insulin in all forms either pen devices or Subcutaneous Insulin Infusion (Insulin pump) is painful, inconvenient and does not achieve the recommended glycaemic goal. Insulin delivery through pulmonary route is rapidly absorbed comparable to subcutaneous injection of two faster acting insulin analogues, insulin lispro and insulin aspart with a much longer duration of action lasting four to six hours. Studies have shown that availability of inhaled insulin as a potential treatment option increases patients’ willingness to add or change to insulin therapy.

Introduction

Subcutaneous injection has been the only route of delivering insulin to patients with diabetes mellitus for the past 85 years, since its discovery by Fredrick G. Banting, Charles H. Best in 1921[1]. Subcutaneous injection is not only painful and inconvenient and not readily accepted by the diabetic patients. At the same time it does not achieve recommended glycaemic control, even with the newer analogue insulins, insulin aspart and insulin lispro. Alternative routes of insulin administration have been studied including dermal, oral, nasal and pulmonary routes. The dream of an “insulin tablet” has not been materialized due to the presence of peptidases in the gastrointestinal tract and rapid degradation of insulin by liver through “first pass metabolism”. Pulmonary application of insulin has become a viable alternative route of insulin administration which has been found comparable or even better than the subcutaneous injection of rapid acting insulin analogues.

Pulmonary route for drug administration:

The pulmonary route has been used for decades to administer drug to the lungs for the treatment of asthma and other local respiratory diseases. This route has also received increasing attention for the treatment of systemic diseases [2] . The lung has inherent advantages for insulin administration because of the vast (50-140 m2, ~500 millions of alveoli) and well-perfused absorptive surface (~5 L blood/min, pulmonary capillary blood volume ~0.25 L) and a thin alveolar-capillary barrier[3]. These conditions allow a fast absorption of peptides into the bloodstream and a rapid onset of action after inhalation, thereby, the lung represents a highly permeable ‘port of entry’ into the blood for insulin macromolecules[4].

Insulin administration through pulmonary route:

Insulin in a given aerosol whether in powder or liquid forms, is unevenly distributed in the lung among particles with various sizes and deposition properties. Thus, the inhalation of insulin cannot be expected to yield 100% of the applied dose. Several studies with inhaled insulin showed a relative bioavailability and biopotency of less than 20%. The reasons for the loss of 90% of insulin during inhalation are not fully understood(5), but the following factors may be considered:
1. Part of the insulin remains in the drug container after inhalation,
2. Some of the insulin adheres to the inner surfaces of the inhaler,
3. Larger particles of insulin get deposited in the mouth, throat and bronchial tree
4. Smaller particles are exhaled without being deposited in the lung alveoli, and
5. Some of the insulin deposited in the alveoli is degraded by macrophages and peptidases.

It is observed that inhaled insulin is more rapidly absorbed, peak concentrations achieved in 49 to 65 minutes compared to the subcutaneous injection of regular insulin whose peak concentrations are achieved in 119 minutes[6]. The time to reach maximum insulin concentration in blood following inhalation (tmax) is comparable to that of subcutaneous injection with the two fast-acting DNA recombinant insulin analogues, insulin lispro and insulin aspart. The duration of action of inhaled insulin lasts four to six hours which is slightly longer than that following subcutaneous administration of insulin lispro or insulin aspart lasting three to five hours but is shorter than that of subcutaneous administration of regular insulin which lasts four to eight hours [7]. This suggests that rapid glycemic control at mealtimes may be achieved with inhaled insulin, similar to that of fast-acting recombinant insulin analogues. Thus patients may be able to inhale a dose 5–10 minutes before a meal to achieve adequate glycemic control rather than the 20–30 minutes necessary with subcutaneous regular insulin injections. Inhaled insulin should be used in combination with a once-daily injection of long-acting insulin because of the shorter duration of action with pulmonary insulin delivery .

A number of insulin delivery systems through pulmonary route are studied and these fall into two main groups: solution and drug powder formulations, which are delivered through different inhaler systems. Exubera, a rapid-acting insulin in powder form, has been studied extensively in patients with type 1 and type 2 diabetes mellitus and now accepted by FDA, US. The AERx Insulin Diabetes Management System delivers a liquid form of human insulin. Other pulmonary insulin delivery systems, including ProMaxx, AIR, Spiros, and Technosphere, are also under study.

Potential risks associated with the inhalation of insulin:

A potential long term risk from the intraalveolar deposition of insulin within the lungs has always been considered, since insulin is known to have growth-promoting properties[8,9]. The high concentration of insulin can stimulate proliferation of local cells via a cross-reaction with Insulin like Growth Factor -1 (IGF-1) receptors or act as a tumour promoter. This is specially so in subjects exposed to carcinogens such as smokers. However, clinical data have not indicated increased cellular proliferation or growth promotion in patients receiving orally inhaled insulin. Wollmer and his colleagues has not observed any substantial change in lung function in patients with type 2 diabetes receiving inhaled regular insulin via the AERx iDMS, in combination with NPH insulin at bedtime[10].
A rise in insulin antibody levels has also been observed with inhaled insulin. The increase is higher in patients with type 1 than with type 2 diabetes specially in the first few months of treatment. However, detailed analysis of clinical data from the patients in these studies showed no correlation of antibody levels with increased glycated haemoglobin, insulin doses, or hypoglycaemia rates. Thus, the appearance of insulin binding antibodies appears not to be correlated to indices of metabolic control and clinical safety.(11).

Acceptability of inhaled insulin:

Results of numerous clinical trials with inhaled insulin have shown a high degree of patient compliance and acceptance(12, 13,14,15). Freemantle et al.[15] examined the impact of the availability of inhaled insulin on patient acceptance. The study was conducted in seven countries with patients with type 2 diabetes The results of this study suggest that the availability of inhaled insulin as a potential treatment may increase patients’ willingness to add or change to insulin therapy.

Conclusions

With the availability of a pulmonary insulin application it can be predicted that the pre-prandial inhalation of insulin will become the first practically applicable alternative to subcutaneous injections in the near future. The clinical-experimental studies show that the pharmacodynamic effects of inhaled insulin are as good as or even better than subcutaneous injection of regular insulin including the new insulin analogues, insulin lispro and insulin aspart, in controlling postprandial hyperglycaemia.

The critical questions regarding the long-term consequences of the inhalation of insulin like changes in lung-function, lung safety and the development of insulin-antibodies, appear to be answered by appropriate long-term studies. This is a topic which requires careful evaluation in view of the potential long-term exposure of patients with diabetes.

References:

1. Banting FG, Best CH, Collip JB et al. Pancreatic extracts in the treatment of diabetes mellitus. 1922. CMAJ.1991; 145:1281-6
2. Laube BL, Benedict GW, Dobs AS. The lung as an alternative route of delivery for insulin in controlling postprandial glucose levels in patients with diabetes. Chest 1998; 114:1734-9
3. Heinemann L, Heise T. Current status of the development of inhaled insulin. Br J Diabetes Vasc Dis 2004; 4(5):295-301
4. Byron PR, Patton JS. Drug delivery via respiratory tract J Aerosol Med 1994; 7:49-75
5. Heinemann L, Heise T. Current status of the development of inhaled insulin. Br J Diabetes Vasc Dis 2004; 4(5):295-301
6. Brunner GA, Balent B, Sendlhofer G et al. Pharmacokinetics and pharmacodynamics of inhaled versus subcutaneous insulin in subjects with type 1 diabetes: a glucose clamp study. Diabetes 2000; 49:A308. Abstract
7. Selam JL. Inhaled insulin for the treatment of diabetes: projects and devices. Expert Opin Pharmacother. 2003; 4:1373-1377
8. Brange J, Owens DR, Kang S et al. Monomeric insulins and their experimental and clinical implications. Diabetes Care. 1990;13:923-954
9. Cefalu WT, Skyler JS, Kourides IA et al. Inhaled human insulin treatment in patients with type 2 diabetes mellitus. Ann Intern Me. 2001; 134:203-207
10. Wollmer P, Clauson P. Evaluation of lung function in patients with type 2 diabetes using AERx insulin diabetes management system (iDMS). Diabetes. 2003; 52:A108 Abstract.
11. Heinemann L, Heise T. Current status of development of inhaled insulin. Br J Diabetes Vasc Dis. 2004; 4(5): 295-301
12. Cefalu WT, Gefland RA, Kourides LA. A three month, multicenter clinical trial of therapy with inhaled human insulin in type 2 diabetes mellitus. Diabetologia. 1998; 41:A226. Abstract.
13. Weiss SR, Berger S, Cheng S et al. Adjunctive therapy with inhaled human insulin on type 2 diabetic patients failing oral agents: a multicenter phase II trial. Diabetes. 1998; 48:A12. Abstract.
14. Cappelleri JC, Cefalu WT, Rosenstock J et al. Treatment satisfaction in type 2 diabetes: a comparison between an inhaled insulin regimen and a subcutaneous insulin regimen. Clin Ther. 2002; 24:552-64.
15. Freemantle N, Blonde L, Bolinder B et al. Inhaled insulin (Exubera) leads to a greater potential acceptance of insulin therapy in patients with uncontrolled type 2 diabetes. Diabetes. 2004; 53:1950. Abstract.34-37

Correspondence Address:

Prof. Th. Premchand Singh. Department of Medicine, Regional Institute of Medical Sciences, Imphal – 795004, Manipur. Email: premthangjam@gmail.com. Phone: +91 9436038030

Diabetes Care

Diabetes

British Medical Journal

NEJM