The Metabolic Arc of life: Prevention is the health challenge of the times

It is one thing to read about changing patterns of disease and treatment. It is quite another to have witnessed those changes personally.

Over the last four decades, I have had the privilege—and perhaps the misfortune—of witnessing one of the biggest transformations in metabolic disease. I began my journey in endocrinology as a resident at the All India Institute of Medical Sciences (AIIMS) in 1984. Diabetes existed, of course, but the scale and nature of the problem were very different. Obesity was hardly considered a public-health issue. Fatty liver was rarely discussed in an endocrine clinic. Insulin resistance was largely a concept found in textbooks and research laboratories rather than something we routinely discussed with patients.

Four decades later, the landscape has changed dramatically. Obesity, type 2 diabetes and metabolic fatty liver disease have emerged as three closely intertwined manifestations of metabolic dysfunction.

When I started training, obesity was not a common condition, even in endocrine clinics. Except for those who were “morbidly” obese, overweight people were rarely considered patients. Obesity was often blamed on a lack of discipline or self-control. In a classroom, there might be only a handful of children who could be labelled “fat”. Today, obesity is increasingly common among children and adolescents—almost one-fourth of children in Delhi’s private schools are overweight; generalised obesity is present in 28.6 per cent and abdominal obesity in 39.5 per cent of adult Indians.

Diabetes, too, was very different. It was predominantly a disease of older adults. Seeing a 30-year-old with type 2 diabetes was distinctly unusual; if you diagnosed a 20-year-old with type 2 diabetes in a final examination, you were almost certain to fail. Today, we routinely see type 2 diabetes in people in their twenties and thirties, and prediabetes—and sometimes overt diabetes—in people barely out of college.

The ICMR-INDIAB study, involving more than 113,000 individuals across India, estimated that about 10.1 crore Indians had diabetes and another 13.6 crore had prediabetes. About 11.4 per cent of adult Indians have diabetes, compared with 1.5 per cent in the 1970s.

Fatty liver has undergone an equally striking transformation. We now routinely see fatty liver on ultrasound in people who have never consumed significant amounts of alcohol. What was once largely regarded as an alcohol-related condition is increasingly recognised as a manifestation of metabolic dysfunction. Even the terminology has evolved, from non-alcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated steatotic liver disease, or MASLD. A recent Council of Scientific and Industrial Research Study of more than 7,000 individuals found that more than one-third were affected with MASLD.

These three conditions are closely connected through a complex web of insulin resistance, visceral fat and abnormal lipid metabolism. When visceral fat accumulates, tissues become less responsive to insulin. The pancreas initially compensates by producing more insulin, allowing blood glucose to remain normal for years despite significant insulin resistance. Eventually, in susceptible individuals, the pancreatic beta cells can no longer compensate adequately. Prediabetes appears, followed by type 2 diabetes.

Visceral fat is not simply an inert store of energy. It produces hormones and inflammatory mediators that can adversely affect several organs. Indians appear particularly prone to accumulating visceral fat, and a person may look relatively lean while harbouring substantial fat around the internal organs. Externally, this may manifest as an expanding waistline, often accompanied by relatively thin arms and legs. The liver is one of the organs in which fat accumulates, and fatty liver may precede diabetes by several years.

Why has this happened?

Our lifestyle has changed profoundly. We have moved from a relatively physically active society to one in which sitting has become part of daily life. Cars and motorcycles have replaced walking, while many cities lack pavements and safe spaces for pedestrians. Long commutes leave little time for exercise. Energy-dense, highly palatable foods are readily available, and delivered within minutes while we lounge in the comfort of our homes. Irregular sleep, stress and air pollution add to the problem.

Economic progress has brought enormous benefits, but it has also changed the way we eat, move and live.

GLP-1s and Beyond

The transformation has not been confined to disease patterns. Treatment has changed almost beyond recognition.

In the 1980s, therapeutic choices for type 2 diabetes were limited. Phenformin was still part of the historical landscape. Sulfonylureas were among the principal oral agents. By the late 1990s, the focus shifted towards glucose control, ushering in an era of glucose-centric management in which much of our effort was directed towards achieving tight glycaemic control. There followed a succession of new therapies, including alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, DPP-4 inhibitors and insulin analogues that greatly enhanced our ability to control blood glucose.

Then came a genuine paradigm shift. We began to understand that treating diabetes was not simply about lowering glucose. Therapies increasingly demonstrated benefits extending to cardiovascular and kidney outcomes, body weight and other complications. SGLT2 inhibitors changed the way we thought about the kidney and heart in diabetes. GLP-1 receptor agonists changed the conversation around weight as well as liver, heart and kidney complications.

We have moved from a handful of glucose-lowering medicines to a therapeutic landscape in which treatment can be guided by cardiovascular risk, kidney function, heart failure, obesity, fatty liver, hypoglycaemia risk, cost, tolerability and patient preference. Diabetes management is no longer simply about treating the glucose number.

Perhaps the most profound change has been our understanding of obesity. For decades, pharmacological treatment had limited success, and lifestyle modification was—and will always be—paramount. Newer anti-obesity medicines have demonstrated something fundamental: obesity is biologically treatable. GLP-1-based therapies act on pathways involved in appetite, satiety and metabolism. Their effects extend beyond the weighing scale, with improvements in glycaemia and several cardiometabolic outcomes. We are also beginning to see benefits in metabolic liver disease.

But it is important not to get carried away. These are medicines, not magic. They have indications, contraindications, adverse effects and costs. They require appropriate selection, dose titration and monitoring. And obesity, like high blood pressure and diabetes, may require long-term treatment.

Moving Upstream

If obesity, insulin resistance, diabetes and fatty liver represent different stages of a metabolic continuum, why wait until the end of that continuum to intervene? We need to move upstream.

The journey begins even before pregnancy. A woman’s health and nutritional status before conception can influence pregnancy and the health trajectory of her child. During pregnancy, excessive maternal weight gain, gestational diabetes and other metabolic disturbances may influence the child’s future risk of obesity and metabolic disease. Conversely, malnutrition during pregnancy may alter foetal programming and increase susceptibility to metabolic disease later in life.

During childhood and adolescence we need less screen time and more outdoor activity. We need healthier school food environments, even if achieving this requires legislation. We also need to address the extraordinary amount of advertising of calorie-dense, nutrient-poor foods directed at children. Eating preferences and habits develop early, and the family as a whole must help create a healthy, non-obesogenic environment. During adulthood, excessive visceral fat needs to be identified early. An increasing waist circumference, hypertension, dyslipidaemia, fatty liver or prediabetes is already sending warning signals about the future.

Instead of waiting for diabetes, we should address obesity and excess visceral fat earlier. Instead of waiting for severe insulin resistance and high blood glucose, we should intervene when unhealthy lifestyles and metabolic risk first become apparent. This has the potential to reduce the subsequent burden of diabetes, fatty liver and their complications.

The World Health Organization’s (WHO) approach to obesity prevention similarly emphasises a life-course strategy, beginning before conception and continuing through pregnancy, infancy, childhood, adolescence, and adulthood.

Prevention does not mean blaming the individual. It is easy to tell someone to “eat less and exercise more”, but adherence to lifestyle advice is notoriously difficult. It is even harder to create a society in which healthy eating and physical activity become the easy choices.

Creating an environment that prevents obesity requires action at multiple levels. It cannot be viewed through the lens of the medical or endocrine clinic alone. A child cannot control what is sold in the school canteen. A teenager cannot control the exposure to food advertising. An office worker may spend hours sitting because of the nature of their job. A city without safe walking spaces makes physical activity difficult.

A person with obesity does not need our judgement. They need our understanding and, when necessary, our medical care.

When I entered endocrinology in 1984, I could not have imagined that four decades later obesity would become one of the defining health challenges of our time, that type 2 diabetes would affect people at such young ages, or that fatty liver would become a common metabolic diagnosis. Nor could I have imagined the extraordinary therapeutic advances that would take place during my professional lifetime. The biggest lesson is not about any particular drug. It is about whether we can prevent metabolic disease before it becomes established.

Can we start with the mother before conception, continue through pregnancy, give the child a healthy beginning, promote healthy habits through adolescence and help adults maintain metabolic health?

By the time a patient walks into our clinic with diabetes, fatty liver, hypertension and obesity, we may be looking at the final chapters of a story that began decades earlier.