Role of Oral Insulin in Treatment of Diabetes

Diabetes Mellitus is a major healthcare problem today, it is a condition marked by hyperglycemia, glycosuria, hyperlipidemia, negative nitrogen balance, and ketonemia. The number of cases of diabetes is increasing rapidly every year, about 537 million adults are diagnosed with diabetes every year. Type-1 diabetes affects 5% of diabetic people which accounts for 20 million cases of diabetes reported every year. About 1.5 million people die every year due to diabetes. Of all these statistical data, oral insulin is an interesting area of research and development in the field of diabetology.

Insulin has saved the lives of millions of people since its discovery in 1922. This hormone is a basic requirement for individuals suffering from type-1 diabetes and is supplied via injections. However, the difficulty associated with subcutaneous administration hinders frequent self-monitoring of glucose.

The need for the oral insulin

  1. Resistance to the insulin injections has been identified as a lack of achievement of target glycemic goals. Both physicians and patients, fear the complexities of the insulin regime, risk of hypoglycemia, weight gain and the insulin prick with insulin therapy.
  2. Oral insulin on the other hand improves the functioning of beta cells, by providing the rest. It helps in preventing diabetes via inducing oral tolerance or immunomodulation.
  3. Oral insulin may enter the liver through the gastrointestinal tract via the portal circulatory system and reduces the chances of its exposure to systematic circulation which abates the excessive weight gain seen with subcutaneous injection.

Barriers to oral insulin

Several physicochemical barriers are present in the gastrointestinal tract.

  • The physiological function of the enzymes present in the GI tract is to break proteins into smaller inactive that can easily overcome the secondary. These barriers are present in the body as a defense against potentially dangerous toxic molecules. Researchers are trying to break this defense mechanism to allow the active protein drugs to cross the barrier and produce desired pharmacological effects.
  • Pepsin, trypsin, carboxypeptidase, and other pancreatic enzymes break the protein into small molecules.
  • The insulin that survives faces a barrier to absorption as well. The intestine has columnar epithelial cells with hydrophobic proteins called occludins, it’s a thick layer of mucus that prevents the absorption of insulin through the tract.
  • Apart from these barriers, this insulin has to enter the liver for first-pass metabolism before reaching the peripheral sites. This direct entry of insulin has been postulated as a physiological advantage.

Approaches to oral insulin

Various approaches have been tried by scientists to overcome the above-mentioned barriers.

  • Insulin has been encapsulated in nanoparticles by mucoadhesive polymers such as chitosan, poly( lactic-co-glycolic acid) (PLGA), and alginate, which prevent the enzymatic degradation and allows its absorption across the epithelial layer of payers patches. This approach depends on the absorption of insulin in the colon.
  • Some of the protease inhibitors such as bacitracin, sodium glycolate, and camostat mesylate, improve the absorption rate and also prevent insulin degradation, thereby increasing its absorption.
  • Insulin can also be modified by PEGylation which changes the insulin pharmacokinetics, prevents enzymatic degradation, and increases its absorption.
  • Permeation enhancer fatty acids such as Zonula occludens toxin (ZOT) and monosodium N-(4-chlorosalicyloyl)-4-aminobutyrate (4-CNAB) are also used. However, these molecules may lead to inflammation and infections in the GI tract.

Recent reports of oral insulin

IN-105 is an insulin analog that has been used orally in the form of tablets and has been modified by linking a single short-chain amphiphilic oligomer, through a covalent non-hydrolyzable amide bond, to the free amino acid group on the Lys-β29 residue of recombinant human insulin. This improves its solubility, stability, and systemic absorption. Solubility is due to PEGlyation while stability is due to steric hindrance.

IN-105 has similar insulin receptor binding and metabolic activity similar to that of human insulin while exhibiting much lower (25-30%) insulin-like growth factor, receptor binding, and mitogenic activity.

Another oral insulin under development known as NN1952 has recently completed Phase 1 studies to study safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy subjects and subjects with type 1 and type 2 diabetes.

Future aspects of oral insulin

Scientists and researchers are working on oral insulin on its bioavailability and other stability-related factors. The physiological stability and bioavailability of oral insulin are low. It may still take years of study and research for this molecule to be available on market for human use.


Ritika Gupta

Ritika Gupta is an MPharm. graduate who is keen on spreading awareness about various unexplored medical fields through her writings.

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