Chapter 48
Obesity and Diabetes — 7
Figure 4.2. Schematic of structures of major cell types in the body at scale. Adapted from Ian Hatton et al., “The human cell count and size distribution,” Proceedings of the National Academy of Sciences of the USA 120, no. 39 (September 2023): e2303077120, https://doi.org/10.1073/pnas.2303077120.
The inflammation that is associated with white adipose tissue occurs throughout the body. In the brain, it’s characterized by activation and recruitment of microglia, the resident immune cells. In the liver, fat tissue, and skeletal muscle, there’s recruitment of macrophages, the innate immune cells, and from the bone marrow release of monocytes into the blood. This coordinated meta-inflammation is the essential biology underpinning of obesity and why it was reclassified as a complex, chronic disease.
Our diet is a key factor for promoting or reducing inflammation. For type 2 diabetes, the benefit of low-carb diets, with 10 to 25 percent of calories from carbs, or even lower, has been amply validated. A systematic review of twenty-three trials indicated a 32 percent increase in remission of diabetes. The intake of milk in people with lactose intolerance (as determined by a lactase LCT gene variant) has been linked to a favorable modulation of the gut microbiome and lower risk of type 2 diabetes. A relationship between the polygenic risk score for type 2 diabetes and titration of risk with a healthy diet has been established in multiple cohort studies.
THE GOOD AND BAD NEWS FOR PUBLIC HEALTH
Historically, obesity was stigmatized. We fat-shamed people because they supposedly didn’t have enough willpower. In 2020, a joint international consensus called for ending the stigma of obesity, and we have since seen obesity increasingly recognized as a chronic disease. It transcends lifestyle factors like nutrition and exercise, and is influenced by genetics, the gut microbiome, the person’s environment, and physiological and socioeconomic factors. We’ve recently learned that the response to GLP-1 drugs can be variable, and there are at least some genetic variations in the receptor that have been discovered that help explain why that’s the case. The researchers who made this discovery suggest the GLP-1 receptor variants should be assessed before using these drugs in people with diabetes. Over 10 percent of people who take GLP-1 drugs for more than a year lose less than 5 percent body weight. A genetic test predicting how well—or not—these drugs will work for someone with obesity is now available.
The significance of the GLP-1 science breakthrough can be appreciated by the long history of failures that preceded it. In the 1990s, a combination drug of two neurotransmitter releasing agents—fenfluramine and phentermine—known as fen-phen, was widely prescribed, even without FDA approval, after a randomized trial showed it achieved an average weight loss of 18.5 pounds compared with 10 pounds in the placebo group. There were over eighteen million prescriptions of the combo in 1996. Soon case reports appeared of people who took fen-phen and then developed valvular heart disease and hypertension of the lung blood vessels (known as pulmonary hypertension). By 1997, the Mayo Clinic documented this occurrence in twenty-four young women, average age of forty-four years, alongside many other reports to the FDA, which led to its withdrawal later that year. Later, a systematic assessment of the drug pointed to about three people in ten developing fen-phen-induced valvular heart disease. This wasn’t the only new drug strategy that backfired with serious safety concerns.