Diabetes Type 2 The SCFAs excreted by the soluble dietary fiber-consuming bacteria in the intestine activate FFAR2 on nearby intestinal L-cells. This stimules these cells to secrete
GLP-1 (i.e., glucagon-like peptide-1) and
PYY (i.e., peptide YY) into the blood. GLP-1 stimulates pancreatic
beta cells to secrete insulin into the blood and inhibits pancreatic
alpha cells from secreting
glucagon into the blood. Since insulin causes cells to take up blood glucose and glucagon causes the liver to release glucose into the blood, FFAR2 activation of L cells lowers blood glucose levels. In addition, PYY and GLP-1 reduce appetite and food consumption. The excreted SCFAs also activate FFAR2 on nearby intestinal K cells to simulate their secretion of
GIP (i.e., glucose-dependent insulinotropic polypeptide). GIP stimulates insulin secretion but, perhaps paradoxically, also stimulates glucagon secretion; however, the net effect of GIP is to reduce blood glucose levels. GIP also slows gastric motility. In addition, both GLP-1 and GIP protect pancreatic beta cells from dying by
apoptosis (see
programmed cell death). A study treated non-diabetic, healthy men with the GLP-1
receptor antagonist (i.e., blocker of receptor activation) exendin(9-39)NH2a (also termed avexitide), the GIP receptor antagonist GIP(3-30)NH2, or both antagonists and challenged them with an oral
glucose tolerance test. Men treated with either agent responded to the tolerance test with modest decreases in blood insulin levels and modest increases in blood glucose levels. However, men treated with both antagonists responded with very low insulin and very high glucose blood levels: their responses were similar to those in individuals with type 2 diabetes. This study shows that
1) the stimulation of the FFAR2 on K and L cells by SCFAs underlies the differences between oral and intravenous glucose challenges defined by the incretin effect and
2) FFAR2 functions to regulate blood insulin and glucose levels. This does not prove that type 2 diabetes is a FFAR2-incretin disease: post-feeding secretion of the
incretins (i.e., GLP-1 and GIP) is impaired in type 2 diabetes, but the impairment appears to result primarily from decreases in the responsiveness of pancreas alpha cells to GLP-1. This conclusion is supported by studies showing that type 2 diabetic individuals who are treated with large amounts of GLP-1 and challenged with intravenous glucose show changes in blood insulin and glucose levels that are similar to those in non-diabetic individuals. and a first-in-kind GLP-1 and GIP agonist,
Tirzepatide, are used to treat type 2 diabetes.
Type 1 Ffar2 gene knockout mice (i.e., mice that have had their
Ffar2 genes removed or inactivated) have decreased pancreatic beta cell masses at birth and throughout adulthood but do not develop diabetes. However, they do develop defective insulin secretion, glucose intolerance (a
prediabetic condition in humans manifested by elevated blood glucose levels), and obesity. Finally, a study of children with pre-type 1 diabetes (base on their having
antibodies against multiple pancreatic islet
antigens) found that children who had low levels of SCFA-producing intestinal bacteria had a higher risk of progressing to type 1 diabetes than those with higher intestinal levels of these bacteria. These results suggest that the activation of FFAR2 by intestinal SCFAs suppresses the development of type 1 diabetes in mice and humans and may do so by reducing the inflammation with injures pancreatic islet cells.
Inflammation FFAR2 is expressed in various cells involved in the development of
inflammatory responses such as neutrophils, monocytes, macrophages, dendritic cells,
regulatory T cells, and
T helper cells. FFAR2 often appears to be involved in suppressing these cells' pro-inflammatory actions and thereby the development of inflammation. For example:
1) compared to control mice,
Ffar2 gene knockout mice developed more severe and unresolving inflammation in
colitis,
arthritis,
peritonitis, and
asthma models of inflammation;
2) germ-free mice, which lack intestinal SCFAs, likewise had severer disease in these colitis, arthritis, and asthma models;
3) in a dextran sulphate sodium-induced model of colitis,
Ffar2 gene knockout mice developed more severe disease than control mice;
4) two studies found that normal mice but not
Ffar2 gene knockout mice fed a prebiotic diet that produces higher intestinal levels of SCFAs were protected from developing
allergic responses to food;
5) the latter study also showed that the prebiotic diet was fully protective in
Ffar3 gene knockout mice); and
6) studies in mice and humans suggest that FFAR2 is involved in suppressing the pancreatic islet inflammation underlying the development of type 1 diabetes (see previous section). Other studies, however, have reported that FFAR2 promotes inflammation. Two studies found that FFAR2
gene knockdown mice had less severe disease in a dextran sulphate sodium-induce colitis model compared to control mice. Notably, a study based on the premise that FFAR2 promotes inflammation examined the effect of GLPG0974, a potent allosteric antagonist inhibitor of FFAR2, on patients with the inflammatory disease
ulcerative colitis. The study progressed through phase I and II
clinical studies that found the drug to be safe (i.e., non-toxic) but ineffective in reducing mild to moderate ulcerative colitis (further development of GLPG609 was terminated). There have been very few studies on FFAR2 and lipolysis in humans. Two studies reported that acetic acid suppressed fatty acid blood levels in humans but did not determine if this effect involved FFAR2. Note that in a mouse model of severe stress, i.e., starvation, FFAR2 activation stimulated lipolysis (see next section on Ketogenesis and ketoacidosis). pregnancy, and the first 28 days after birth (i.e., the neonatal period); this form of ketogenesis is associated with modest elevations in the blood levels of the ketone bodies and, due to their increased release from adipose tissue, fatty acids. The circulating ketone bodies and fatty acids serve as nutrients to sustain the functioning of critical organs such as muscle, heart, kidney and brain when blood glucose levels are too low to do so. Similarly, patients undergoing
hemodialysis that uses a hemodialysis solution containing acetic acid have an increased risk of becoming hypotensive compared to patients dialyzed with an acetic acid-free solution. Long-term oral intake of FFAR2-activating SCFAs also lower blood pressure in mice and humans. Furthermore,
FFAR2 gene knockout mice developed perivascular
fibrosis (which is an indicator of blood vessel disease), higher end-diastolic
blood pressures, and higher
pulse pressures. Mice lacking both FFAR2 and FFAR3 had exaggerated responses to hypertension; this seems to happen via changes to the gut epithelial barrier and activation of the immune system. Finally, in the angiotensin II–infusion model of hypertension, mice had reduced levels of FFAR2 in their kidney tissues compared to control mice These findings suggest that FFAR2 functions to reduce blood pressure as well as
hypertension induced vascular disease in mice and humans and support further studies to examine these relationships.
1) One study found that FFAR2 levels were elevated in human
stomach and
colorectal cancers although another study reported that FFAR2 levels were markedly deceased in human colorectal cancer. These results suggest that FFAR2 may promote the development and/or progression of human stomach cancer but its impact on human colorectal cancer requires further study. This study suggests that FFAR2 inhibits the development and/or progression of inflammation-associated colon carcinoma in mice; its role in human inflammation-associated colorectal cancer (e.g., colorectal cancer developing in
ulcerative colitis) has not been clarified.
4) Butyric acid inhibited the proliferation of and triggered
apoptosis in cultured human
A549 lung cancer cells; further studies in A549 as well as
H1299 human lung cancer cells found that propionic acid inhibited their stimulated migration, invasiveness, and colony growth in cell culture assays but did not do so in
FFAR2 gene knockout A549 or H1299 cells. and human bladder cancer NaB cells but neither study determined if their actions involved FFAR2.) Further studies are needed to confirm and broaden these preliminary findings and extend them to other types of cancer. and mediate inflammatory responses to, e.g., bacterial invasion as well as the pathological inflammations which underlie many neurological diseases. With somewhat less evidence, other studies have suggested that SCFRs may suppress the development and/or progression of human
autism,
schizophrenia,
vascular dementia,
strokes, pathological anxiety and depression disorders, and
postoperative cognitive dysfunction. Some of these studies mention the possibility that SCFA-induced activation of FFAR2 suppresses these diseases and disorders but give no evidence to support this. The studies often do suggest that the SCFAs act by various other mechanisms to achieve their neurological effects. Furthermore, the role of SCFAs in humans with these diseases may be unclear. For example, two extensive reviews found that studies on the role of intestinal SCFAs in multiple sclerosis patients were inconclusive. There is a need to define the precise roles of SCFAs, FFAR2, and the other proposed causal factors in these neurological diseases and disorders.
2) Injection of acetic acid into the
peritoneum 1/2 hour before or 6 hours after injection of
Staphylococcus aureus bacteria into the bloodstream of mice reduced signs of severe disease, the amount of body weight lost, and the numbers of bacteria recovered from the liver, spleen, and kidneys; these reductions did not occur in
Fffar2 gene knockdown mice. And,
3) higher circulating blood cell levels of FFAR2
messenger RNA were associated with higher survival rates in patients with
sepsis, i.e., disseminated bacterial infections, compared to patients with lower levels of blood cell FFAR2 messenger RNA. These studies suggest that FFAR2 reduces the severity of the cited bacterial infections in humans and mice and recommend further studies on the roles of FFAR2 in these and other bacterial infections. 4-CMTB and Compound 58 acted to block the ability of the sialic acid-bound virus to enhance endocytosis. ==FFAR2-FFAR3 receptor heteromer==