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Is non-injectable insulin the future of diabetes management?

Dr. Rajesh Jaria
Wednesday, January 12, 2022, 08:00 Hrs  [IST]

Politics is intrinsic to every human life! Politicians achieve what others struggle to achieve, and like Rhett Butler; always wear the best tie and suit, ride the best horse and….receive the best therapy.

Every leader is a politician but every politician is not a leader. Elizabeth Hughes' father Charles Evans Hughes was politically so powerful, his daughter was one of the first to receive insulin injections from Canadians Banting & Best; 1923 Nobel Prize winners for discovering insulin.
Elizabeth went on to lead a normal life, receive a college degree, marry, deliver 3 normal children and by the age of 73, she received over 42,000 insulin injections. In those 58 years (21,170 days), Elizabeth remained silent on diabetes, from a guilt, it is speculated; as had she not received the insulin, a Canadian child who was likely to be succumbed to diabetes would have received it.

The "Ifs" of history walk in our minds, but what counters historical ignominy is scientific progress. From the 1923 limitedly available insulin, squeezed from pig pancreas and causing large skin blisters where delivered, to unlimited recombinant DNA tech human insulin with near imperceptible delivery; real human miseries that have been fought and reversed, are indeed legend. Mothers would see their children, melt away to shriveled bone, as lack of insulin would eat away all protein in the body and throw it into the urine. Insulin helps glucose to enter human body cells which then use that glucose to produce energy. If insulin is absent, the body burns protein, which means muscle cells. Muscle cells are precious, intrinsic to vital functions such as movement, postural support, breathing, and thermogenesis and skeletal muscle cells regenerate, but very sluggishly. [Greek; diabetes: siphon - to pass through. Latin; mellitus: honeyed or sweet. Excess sugar found in blood and urine, known in the 17th Century as the "pissing evil"].

High blood sugar adds misery by making diabetics prone to infections. Do recall that Insulin was discovered in early 1920's and the first antibiotic was delivered by Alex Fleming much later in 1928. Desperately thin, super low on energy, usually suffering from throat lung infections and repeatedly using the toilet passing infected, laced with sugar urine, diabetics did not enjoy glorious sunshine filled mornings, lived miserable life's that often ended early, especially if the diabetes was Type I.

Diabetes is classified under the headings of Type 1 and Type 2, hybrid and other types. Type I, is essentially a complete lack of insulin due to ß-cell destruction. The second or Type 2 in addition to varying degrees of ß-cell dysfunction has resistance to insulin (effectively reduced insulin efficacy) with the body attempting to compensate by overproduction and thence overworking the pancreas causing its early senescence. In essence it is defective insulin secretion, insulin action, or both, and disturbances of carbohydrate, fat and protein metabolism.

The final common path of this condition, believed to have archeological mention 3500 years ago, remains an increased value of blood sugar, the effects of which, a remarkable study - the UKPDS, delineated and characterized. It clarified what normal blood sugar levels should be, in fasting [<126mg/dl] and in the post having had a meal state [<200mg/dl] as well as in between at any random moment. Diabetes obviously has different effects when controlled and uncontrolled. Uncontrolled, it is devastating in its immediate effect with a reduced immunity, more infections especially genital yeast infections, thirst and weight loss, sleep disturbances with increased urine frequency (polyuria) and a possible life-threatening acidosis from unbridled burning of protein and the ketones thus produced being acid.

Long term effects are more disastrous, the mainstay of which is microvascular damage leading to blindness (retinopathy), kidney failure (nephropathy), nerve damage (neuropathy), an increased propensity for harmful vascular events involving the heart, peripheral arteries, cerebrovascular disease, obesity, cataracts, erectile dysfunction, and nonalcoholic fatty liver disease and infectious diseases, such as tuberculosis.

Diagnosis of diabetes is through tests like fasting plasma glucose [>126 mg/dl]; 2-hour post-load plasma glucose after a 75 g oral glucose tolerance test (OGTT) [> 200 mg/dl]; HbA1c [> 6.5%] [HbA1c; glycosylated hemoglobin: a value that correlates with sugar values over the last 3 months]; and a random blood glucose [> 200 mg/dl] in the presence of signs and symptoms of diabetes. Such a diagnosis has implications beyond health; affecting employment, health and life insurance, driving status, social opportunities, and other cultural, ethical and human rights consequences.

The etiology of diabetes described as defective insulin secretion/sensitivity is rather simplistic, as the defects are complex and ill understood. Few specific defects have been identified e.g., genetic abnormalities; a complete etiological mechanism involves a highly complex interplay of genetic, epigenetic (non-gene effects on gene), proteomic (protein expression) and metabolomic (chemical reactions) processes. Identifying these abnormalities will help, but at present, limited knowledge hinders development of a useful classification with the field of pharmacogenomics extending a classic example. Studies of associations between specific genetic variants and drug response returned small and inconsistent results and the key to the complex mystery remains elusive.
As usual, we remain a country chasing a silver lining where our diabetes cloud, computes India, as the diabetes capital of the world, with 72.9 million adults living with diabetes in 2017 (up from 40.9 million in 2007) with a clear higher prevalence in urban areas. 9.3 per cent senior citizens living in India's rural areas are diabetic as per a study by the Union Ministry of Family and Health Welfare (MoFHW) published on January 6, 2021. Researchers estimate 57 per cent of cases remain undiagnosed.
Several theories attempt to explain the rapid increase in diabetics in India. Indians have a higher fat to muscle ratio, leading to delayed insulin excretion, increased metabolic load and insulin resistance. General awareness about diabetes is low. Farming practices & public distribution systems offer rural communities low cost food to improve nutrition. Research does suggest these systems cater commercially viable crops which are calorie dense and contain fewer nutrients than traditional foods. Traditional foods are being replaced by polished white rice, refined sugar and high glycemic index foods which cause spikes in blood glucose levels. Urbanization with its sedentary lifestyle is an added disadvantage while pollution does add its own two-bit.

All research has proven three facts:
1) Diabetes needs to be treated aggressively to maintain sugar values within normal levels.
2) The earlier the treatment initiated and sugar maintained in normal range, lesser will be long term complications.
3) Treating diabetes is not limited to sugar value normalcy but needs a global approach to preventing metabolic damage.

Treatment of diabetes currently remains to a major extent a glucocentric approach. Patient visit a doctor, who prescribes medications and till sugars remain normal the patient does not follow up. Once sugar targets fail to maintain the patient again visits the doctor who hikes up therapy. With every failure the cycle repeats till the patient goes on to insulin therapy creating the myth - once insulin is started it remains for life!! A far superior "pathophysiologic" approach is taking root, targeting to treat successfully by slowing/delaying the metabolic progress of diabetes. A short intensive Insulin regimen for e.g. may result in improvement in insulin secretion and sensitivity to drug therapy

The main treatment options are, with medicines and insulin. Oral medicines come in few broad categories. Some induce increased insulin secretion, some increase sensitivity to insulin, some reduce sugar absorbed from food and some increase excretion of sugar in urine. Some medicines can help reduce pancreatic beta cell failure. Each of these has a place in patient treatment but which combination to use is strictly the domain of the treating physician. Combinations chosen cannot always be ideal as they depend on multiple, often confounding factors, but broadly, combinations that help target diabetes pathophysiology, may in the long term prove superior.

The vaccine race of the Covid pandemic gave a live example of how newly discovered medicines reach the masses. Similarly; Insulin was discovered in 1921, and first used in humans in January 1922 in Canada. In Europe insulin was first used in August 1922 with an absent commercial production strategy in war-torn Europe, and each country having to find its own way to make insulin available for its people. Great Britain, Denmark, and Poland were among the first to produce their own insulin with a personal story behind arrival of insulin to each of these countries. Today insulins are available in a wide spectrum of ultra-short acting, short acting, long acting basal and ultra-long acting basal insulin. All these are human insulins, some with changes added at the molecular level to change their duration of action.

Taking this race ahead is the search for non-injectable insulins as the need to take injections remains the greatest barrier to insulin use. The possibility of a non-injectable insulin formulation is closer than ever before but has not yet achieved reality. Oral delivery is the simplest, but insulin, cannot survive passage through the stomach or the gut because the gut cannot directly absorb molecules so large without fragmenting them and causing loss of function. Researchers did develop an ingestible, self-orienting, millimeter-scale capsule applicator [SOMA] that can be swallowed and contains a spring-loaded needle with compressed, freeze-dried insulin. When swallowed, it is weighted to ensure the needle enters stomach skin (mucosa), inject insulin and the outer covering is dissolved. In vivo studies conducted in rats and swine support the applicator's safety and efficacy; but it remains experimental.

In November 2019, Oramed Pharmaceuticals reported results for its trial of an oral human insulin. 269 adults with type 2 diabetes, demonstrated safety and efficacy for ORMD-0801, the company's lead oral insulin candidate, as well as a clinically meaningful reduction in HbA1c when compared with placebo. The drug has the potential to be the first commercial oral insulin capsule for the treatment of diabetes.

Novo Nordisk reported results earlier of oral insulin 338 (I338), a long-acting, basal insulin analogue formulated in a tablet with the absorption-enhancer sodium caprate, and safely improved glycemic response in 25 insulin-naive adults with type 2 diabetes, similar in action to injectable insulin. Further development was however discontinued because I338 doses were high and production of required quantities was deemed commercially unviable.

An inhaled rapid-acting mealtime insulin (Afrezza), was approved by the US FDA in 2015. It was able to address after meal sugar rise. The first US FDA-approved powdered inhaled native human insulin (Exubera, Pfizer) was withdrawn from the market in 2007, with hypoglycemia (lower than normal sugar) the most common side effect, and frequent glucose monitoring being a self-destructive necessity. The inhaled route saw respiratory adverse effects including infection, cough, pharyngitis, rhinitis and a statistically significant decline in pulmonary function. Afrezza with superior delivery methods, had similar side effects, with added risk of lung cancer and acidosis.

Generex's Oral-Lyn is a liquid formulation of human insulin that is sprayed into the mouth using its proprietary RapidMist device. In the mouth the insulin is absorbed via the buccal mucosa, an area with a rich vasculature. Reformulated Oral-lyn-2 for Type 2 diabetes and Altsulin for the treatment of Type 1 diabetes are in development.

Science follows Newtonian physics. Effort required for the first few steps is steep and exacting. As the ball gathers speed, the eventual outcomes are no less than an oxymoronic real-magic. Non-injectable insulins though having had a slow start, have not been abandoned by the infinitesimally tiny but immensely effective trait called 'human effort'. As long as this effort continues, the magic becoming a reality, is an eventuality.    

(Author is consultant, Internal Medicine, at P D Hinduja Hospital and Medical Research Centre, Khar, Mumbai)


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