In This Issue of Diabetes

A series of butyrate-producing bacteria in the human intestine appear to be associated with various measures of insulin homeostasis and prevalence of dysglycemia, according to Cui et al. (p. 2438). Specifically, it appears that while most butyrate-producing bacteria appear to be metabolically beneficial, this is not necessarily the case for some species. According to the authors, this suggests any sort of therapeutic measures (when they exist) toward preventing or treating diabetes via butyrate-producing bacteria will need to be targeted toward specific taxa rather than all such bacteria. The findings come from a cross-sectional analysis of associations between 36 butyrate-producing taxa/species and a series of measures of insulin homeostasis and dysglycemia determined via oral glucose tolerance tests. Just under half of 353 participants were classified as having dysglycemia (i.e., prediabetes or diabetes), while the remainder were classified as having normal glycemia. At the level of genera, Coprococcus was associated with higher insulin sensitivity and disposition index and a lower rate of dysglycemia. Conversely, Flavonifractor was associated with lower insulin sensitivity and disposition index and a higher rate of dysglycemia. At the species level many, but not all, bacterial species were associated with improved insulin sensitivity and disposition index. Other species had a negative association with insulin sensitivity and disposition index. In contrast, few associations were observed between species and insulin clearance or insulin secretion. Possible explanations for the adverse associations with glycemic outcomes, the authors suggest, include taxa with metabolic processes that counteract the effects of butyrate. Potential virulence factors in butyrate-producing species could also have negative effects as well as the possibility of co-occurring butyrate-consuming bacteria that produce harmful metabolites. Commenting more widely, author Mark O. Goodarzi said, “There is great hope that future prevention or treatment methods for diabetes will involve modulating the gut microbiota. Studies such as these that pinpoint which species to target are critical to the success of future microbiome-directed therapies.”

A low-molecular-weight calcium-binding protein called S100A6 appears to act as a messenger protein that mediates β-cell dysfunction in nonalcoholic fatty liver disease (NAFLD), according to Dogra et al. (p. 2284). Specifically, it appears that it impairs glucose-stimulated insulin secretion in pancreatic β-cells, potentially explaining why the development of type 2 diabetes is such a common outcome of NAFLD. While the research is still early stage, the authors suggest that the S100A6 protein serves as a biomarker for type 2 diabetes risk. They also propose that neutralizing circulating S100A6 or antagonizing its receptor is a therapeutic route to restoring β-cell function in NAFLD. The findings come from an investigation involving data from human patients and in vitro, ex vivo, and in vivo experiments with mice and various cell lines. The core aim of the studies was to explore the pathophysiological relevance of the S100A6 protein in fatty liver-associated stress. They found that serum expression levels of the S100A6 protein were elevated in human NAFLD patients as well as in a high-fatdiet–induced mouse model of NAFLD. Elevated levels of the protein also appeared to associate with increased lipogenesis and potentially adverse β-cell function. In a series of gain- or loss-of-function experiments, the authors also found that intracellular lipid stress (induced in three different ways) led to increases in hepatic and systemic levels of S100A6. The expression of carbohydrate response element-binding protein, or ChREBP, was also enhanced, with further experiments confirming that it regulates the expression of S100A6. “Our study also supports that neutralizing circulating S100A6 and/or antagonizing its receptor… could be therapeutic in restoring β-cell function in NAFLD,” the authors suggest. Author Prosenjit Mondal added, “The findings may offer new diagnostic and therapeutic tools for fatty liver-induced diabetes. This study further opens up the possibility of discovering novel mediators, soluble and exosomal proteins, and microRNAs that could adversely or favorably modulate the hepato–pancreatic axis.”

Mesencephalic astrocyte-derived neurotrophic factor, or MANF, is a key regulator of hypothalamic neurons that express proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated factor (i.e., POMC neurons). According to Tang et al. (p. 2344), this sets up MANF as a key mediator of whole-body energy balance and, potentially, a route toward longer-term medical treatment of obesity, of which none exist currently. The findings come from studies in mice that variously looked at the effects of deletion or overexpression of MANF in POMC neurons and its effects on diet-induced obesity. The authors also looked at how MANF might affect energy homeostasis (i.e., energy balance and intake) and any potential underlying mechanisms. They found that mice lacking MANF in POMC neurons experienced greater body weight gain than controls when fed either a normal or high-fat diet. Conversely, mice with overexpression of MANF specifically in POMC neurons were protected against obesity. Working through potential mechanisms, they also identified that deficiency of MANF in POMC neurons induced endoplasmic reticulum stress in the hypothalamus. This appeared to affect leptin signaling and ultimately POMC expression, which in turn impaired thermogenesis in brown adipose tissue. Cold exposure, which can induce thermogenesis in brown adipose tissue, had attenuated effect in mice with the MANF knockout. In contrast, mice with MANF overexpression exhibited brown adipose thermogenesis and were protected against obesity. According to the authors, this occurred via improved leptin signaling in the hypothalamus and increasing sympathetic innervation and activity in brown adipose tissue. Commenting further, author Jinhan He said, “Previous studies have found that decreased MANF expression is associated with metabolic disorders, including obesity. The role and mechanism of hypothalamic POMC neuron-expressed MANF in regulating systemic energy homeostasis elucidated in the present study not only further confirms that MANF can be an important therapeutic target for obesity and related metabolic disorders but also provides a strong mechanistic basis.”

Gestational diabetes mellitus (GDM) appears to be characterized by differential expression of five specific plasma exosomal miRNAs, according to Ye et al. (p. 2272). Combined with classical risk factors for GDM, the addition of the circulating exosomal miRNAs improved predictive power for GDM as early as 10–16 weeks of gestation. Previous studies have shown associations between exosomes and GDM but largely only on an individual level and not from the perspective of trying to predict GDM earlier than usual diagnoses at 24–28 weeks of gestation. The findings come from a study that initially used next-generation sequencing to identify miRNAs that were differentially expressed in 12 pregnant women with GDM and a further 12 pregnant women with normal glucose tolerance. The authors then validated the initial findings in a prospective cohort of ∼100 pregnant women with GDM and a further ∼100 with normal glucose tolerance. They found that, after validation and verification with real-time quantitative PCR analysis, five miRNAs were differentially expressed in GDM compared to normal glucose tolerance. Specifically, one was upregulated (miR-423-5p) and four were downregulated (miR-122-5p, miR148a-3p, miR192-5p, and miR-99a-5p) in GDM. To then identify potential mechanisms involved, the authors looked at associations between clinical characteristics of glycemia and the dynamics of miRNAs, finding a series of correlations between them. KEGG pathway analysis also revealed the likely pathways involved, finding a series linked broadly to glucose metabolism and insulin signaling. Cell-based studies involving overexpression or mutagenesis then revealed further mechanisms and potential downstream mRNA targets of the exosomal miRNAs. “Our results illustrated that these circulating exosomal miRNAs improved the early prediction of GDM, together with classical risk factors,” they write. “The predictive power of our study outperforms previous predictions using lipid biomarkers, random plasma glucose, or serum metabolites.”