HomeENGLISH MAGAZINEWhy some obese people get diabetes and others don't? Blame on how...

Why some obese people get diabetes and others don’t? Blame on how microbiota settles with your diet

Type 2 diabetes is a serious metabolic disease that affects roughly one in 10 Americans. Formerly known as adult-onset diabetes, it is a chronic condition affecting the way the body metabolizes glucose, a sugar that’s a key source of energy. This type of diabetes is frequently associated with obesity. For some patients, that means their body does not properly respond to insulin – it resists the effects of insulin, the hormone produced by the pancreas that opens the door for sugar to enter cells. In the later disease stages, when the pancreas is exhausted, patients don’t produce enough insulin to maintain normal glucose levels. In either case, sugar builds up in the bloodstream and, if left untreated, the effect impairs many major organs, sometimes to disabling or life-threatening degrees. A key risk factor for type 2 diabetes is being overweight, often a result of eating too much fat and sugar in combination with low physical activity.

Obesity is a very serious public health problem, not only because it already affects a good portion of adults, but because the phenomenon of childhood and adolescent obesity is constantly and worryingly increasing; and it is something that could very well be avoided with greater cultural pressure and responsibility on the part of parents. However, there has always been a question that has haunted scientists and experts in diabetes and endocrinology: why do only some obese patients develop diabetes and others do not? Researchers at Oregon State University might have an answer or at least part of it. Drs Andrey Morgun and Natalia Shulzhenko of OSU and Giorgio Trinchieri of the National Cancer Institute developed a novel analytical technique, multi-organ network analysis, to explore the mechanisms behind early-stage systemic insulin resistance. The scientists sought to learn which organs, biological pathways and genes are playing roles.

Findings showed that a particular type of gut microbe leads to white adipose tissue containing macrophage cells – large cells that are part of the immune system – associated with insulin resistance. As everyone knows, white adipose tissue is the main type of bodily fat. According to their preliminary analysis and experiments, a high-fat/high-sugar diet primarily acts in white adipose tissue by driving microbiota-related damage to the energy synthesis process, leading to systemic insulin resistance. The human gut microbiome features more than 10 trillion microbial cells from about 1,000 different bacterial species. Drs. Morgun and Shulzhenko, an associate professor in OSU’s Carlson College of Veterinary Medicine, in earlier research developed a computational method, transkingdom network analysis, that predicts specific types of bacteria controlling the expression of mammalian genes connected to specific medical conditions such as diabetes.

In the new study, the scientists relied on both transkingdom network analysis and multi-organ network analysis. They also conducted experiments in mice, looking at the intestine, liver, muscle and white adipose tissue, and examined the molecular signature – which genes were being expressed – of white adipose tissue macrophages in obese human patients. According to previous research that has pointed the finger at the eating lifestyle defined as the “Western diet”, the Oregon State University team also concluded that it is all in the ability of the diet to modify the microbiota and induce a real risk of developing diabetes. Adipose tissue has a predominant role in systemic insulin resistance, and we characterized the gene expression program and the key master regulator of adipose tissue macrophage that are associated with insulin resistance. Through their model, researchers established that diabetes induced by the western diet is characterized by microbiota-dependent mitochondrial damage.

Due to mitochondrial impairment, cellular oxidative phosphorylation becomes maloperative and does not allow the use of fatty acids as an energy substrate. Their redirection towards resynthesis leads to the enlargement of fat cells and the aggravation of insulin resistance. This is how professor Shulzhenko explained the undelying mechanisms: “We previously showed that the bacterium Romboutsia ilealis worsens glucose tolerance by inhibiting insulin levels, Now, we add that the Oscillibacter valericigenes, a microbe enriched by a western diet, causes an increase of the insulin-resistant adipose tissue macrophage. Possibly Oscillibacter is likely not the only microbial regulator for expression of the key gene they identified – Mmp12 – and that the Mmp12 pathway, while clearly instrumental, is probably not the only important pathway, depending on which gut microbes are present”.

Scientists then tested the functional effects of macrophage metalloprotease 12 (MMP-12), and found that its genetic deficiency or pharmacological inhibition improved glucose metabolism in conventional, but not in germ-free mice. Direct MMP12 treatment of cultured adipocytes, finally, induced insulin resistance. And all the spark is in the membrane proteins of Oscillibacter bacteria. Some of its surface proteins are ligands for the immune tolerance receptor TLR2, which is expanded in white adipose tissue macrophages by a diet rich in carbohydrates and fats. Bacterial ligands activate TLR2 which, in turn activates the MYD88-ATF3 signaling patway to induce the expression of MMP12 in macrophages. This way inflammation and insulin-resistance take place. And all of it started in the gut. In their previous research, the researchers proved that by repopulating the flora with Lactobacillus strains, the inflammatory reaction is reduced and tends to rebalance the state of insulin resistance induced by a western diet.

This is well reconciled with the initial theory of 15 years ago according to which the microbiota with its toxins, such as lipopolysaccharide (LPS) would be able to induce inflammation of the intestine and certain target organs such as the liver and, starting from insulin resistance , lead to the onset of type 2 diabetes.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Advised in this website

Keymaster and gatekeeper microbiota: how food and cells lead us to disease directly form the gut (04/02/2022)

Inflammation, immunity, diet and sleep: who regulates who? (23/05/2020)

Innate immunity connected to gut microbiota: the guests teach the host how to behave (29/01/2020)

Microbiota: western diet and gut bacteria trying to keep the balance (28/12/2018)

Crohn’s, immunity and bacteria: who’s behind who? (04/01/2018)

Scientific references

Li Z et al. J Exper Med. 2022 Jul 4; 219(7):e20220017.

Logan IE et al. Mol Nutr Food Res. 2021; 65(21):e2100389.

Rodrigues RR et al. Nature Commun. 2021; 12(1):101.

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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento enzimaticamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (Leader of the R&D for the partnership CoFood s.r.l.) - Autore di articoli su informazione medica e salute sul sito www.medicomunicare.it (Medical/health information on website) - Autore di corsi ECM FAD pubblicizzati sul sito www.salutesicilia.it
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