What causes obesity and diabetes?

When we eat, we are stocking up on glucose, a molecule that is fundamental for our cells to function. Glucose is so crucial that our bodies evolved a mechanism to store it when food is available in plenty. The excess stock is stored in the form of lipid droplets that can be converted back to glucose at times when food is scarce. This is where the hormone insulin comes into play, explained Anil Gaikwad, a pharmacologist at Central Drug Research Institute, Lucknow.

“Insulin secretion is a signal to cells to mop up excess glucose from the bloodstream. As long as the normal feeding and fasting cycles are maintained, our cells are functionally responsive to insulin.” The trouble is when cells develop insulin resistance.

With the Industrial Revolution, cheap quality food became easy to access. This, coupled with our sedentary lifestyles, has resulted in an imbalance between our energy intake and usage. This is likely why there is an obesity epidemic in the world — according to the World Obesity Federation Atlas, 11% of Indian adults will be obese by 2035.

In such conditions, there is an oversupply of glucose in the bloodstream and the body is forced to maintain high levels of insulin to control the situation. Beyond a point, cells become desensitised to the insulin, a scenario known as insulin resistance. “With insulin resistance, there is an increased pressure on the beta cells of the pancreas to produce more insulin. This vicious cycle exhausts the beta cells, eventually leading to its death,” said Gaikwad. This is the process that underlies the transition of a person from being insulin-resistant to prediabetic. “When approximately 40% of the beta cells are exhausted and unable to produce the required quantity of insulin, a person is declared diabetic,” he added.

How can the new drugs help?

The active component of the two Eli Lilly drugs Mounjaro and Zepbound is called tirzepatide. Tirzepatide is delivered subcutaneously via an injection given weekly. It works by acting as a ‘dual agonist’. This means that it can mimic two naturally occurring molecules: gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1).

“GIP and GLP-1 are peptides that are released following ingestion of fats and/or carbohydrates. They stimulate the release of insulin, and help increase insulin sensitivity in adipose and skeletal tissue,” said RNV Krishna Deepak, a computational structural biologist at Azim Premji University, Bengaluru.

Being an agonist of these two peptides, tirzepatide can activate the same pathways as them.

Deepak added that GIP and GLP-1 (and therefore tirzepatide, their synthetic analogue), also have other physiological effects including slowing gastric emptying and promoting satiety. “The patient feels fuller for longer and in turn eats less, resulting in weight loss,” he says. This is how tirzepatide helps those with insulin resistance, a group that includes obese and diabetic individuals.

What sets tirzepatide apart?

Tirzepatide is not the only drug to use this strategy to combat diabetes and obesity. Semaglutide, marketed by the company Novo Nordisk, is also a GLP-1 agonist. This drug is already available in India for diabetes management. Like tirzepatide, semaglutide is also effective for weight loss, but in a higher dose (known by its brand name Ozempic). However, its usage for obesity has not yet been approved in India. The edge that tirzepatide has over semaglutide is its property as a dual agonist; not only does it activate the GLP-1 receptor, it also activates the GIP receptor.

Interestingly, there may already be a newer drug that goes one step further than tirzepatide in the offing. Called retatrutide, this works as a ‘triple agonist’, meaning it targets a third receptor, GCGR, besides the GIP and GLP-1 receptors. Studies show that retatrutide may be a better alternative to semaglutide and tirzepatide, but it has some way to go before being approved by a regulatory authority.

Is tirzepatide a silver bullet?

No. “Tirzepatide has received marketing authorisation for type-2 diabetes mellitus in India as an adjunct to diet and exercise to improve glycemic control in adults with type-2 diabetes,” clarified a spokesperson for Eli Lilly. “Diet, exercise and lifestyle modification are the cornerstone of type-2 diabetes management and any active drug indicated for type-2 diabetes is an add-on to diet and lifestyle.”

So far, the most common side effects of taking tirzepatide seem to be nausea and vomiting.

It is also important to know that the medications once launched are unlikely to be affordable to most Indians. When asked about affordability, the spokesperson commented: “We believe tirzepatide will be competitively and appropriately priced based on the efficacy of the medicine and overall lower risk-benefit ratio as observed in phase 3 clinical trials.” While they declined to mention any specifics, a Business Insider report has said that it is likely to be priced at ₹20,000 for each weekly dose.

Nandita Jayaraj is the co-author of Lab Hopping: A Journey to Find India's Women in Science, which explores the gender gap in Indian science. The views expressed are personal