Rethinking the role of the brain in glucose homeostasis and diabetes pathogenesis

Brown, Jenny; Scarlett, Jarrad; Schwartz, Michael W.

doi:10.1172/jci130904

Cited by 26 publications

(27 citation statements)

References 22 publications

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“…We recently reported that, in Lep ob/ob mice and other rodent models of T2D, sustained diabetes remission can be achieved by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) 4 , and the hypothalamus has been identified as the brain area responsible for this FGF1 effect 5 . While this finding is in line with accumulating evidence supporting a key role for the hypothalamus in glucose homeostasis, our current understanding of glucoregulatory neurocircuitry is limited 6,7 . Most of this work is focused on hypothalamic neurons with glucose-sensing properties 8 , but many glial cell types are also potential targets for the hypothalamic action of FGF1, since tanycytes and astrocytes are implicated in glucose homeostasis 9,10 and since glial cell responsiveness to FGF ligands is well documented 5,11,12 .…”

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confidence: 70%

Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission

et al. 2020

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In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.

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confidence: 70%

Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission

et al. 2020

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“…Furthermore, we postulate that this pathogenic sequence begins with or is exacerbated by an impaired ability of the brain to accurately sense the circulating glucose level (i.e. a form of 'brain glucose resistance') [64] (Fig. 1).…”

Section: Reconsidering the Link Between Obesity And Type 2 Diabetesmentioning

confidence: 99%

Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes

2020

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Despite a rapidly growing literature, the role played by the brain in both normal glucose homeostasis and in type 2 diabetes pathogenesis remains poorly understood. In this review, we introduce a framework for understanding the brain's essential role in these processes based on evidence that the brain, like the pancreas, is equipped to sense and respond to changes in the circulating glucose level. Further, we review evidence that glucose sensing by the brain plays a fundamental role in establishing the defended level of blood glucose, and that defects in this control system contribute to type 2 diabetes pathogenesis. We also consider the possibility that the close association between obesity and type 2 diabetes arises from a shared defect in the highly integrated neurocircuitry governing energy homeostasis and glucose homeostasis. Thus, whereas obesity is characterised by an increase in the defended level of the body's fuel stores (e.g. adipose mass), type 2 diabetes is characterised by an increase in the defended level of the body's available fuel (e.g. circulating glucose), with the underlying pathogenesis in each case involving impaired sensing of (or responsiveness to) relevant humoral negative feedback signals. This perspective is strengthened by growing preclinical evidence that in type 2 diabetes the defended level of blood glucose can be restored to normal by therapies that restore the brain's ability to properly sense the circulating glucose level.

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“…The regulatory factors that create pressure gradients are in general divided into three categories; myogenic, neural, and humoral. [25][26][27] Stable fetal systemic blood glucose may be achieved primarily by flow distribution between liver and DV, but also by adjustment of liver metabolism. Animal studies indicate that in the case of hypoglycemia the fetal liver may induce gluconeogenesis or glycogenolysis.…”

Section: Discussionmentioning

confidence: 99%

The impact of umbilical vein blood flow and glucose concentration on blood flow distribution to the fetal liver and systemic organs in healthy pregnancies

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Glucose is a major energy substrate for the fetus, including liver, heart, and brain metabolism. The umbilical vein (UV) blood flow supplies the fetal liver directly from the placenta, whereas a fraction is shunted via ductus venosus (DV) to the fetal systemic circulation bypassing the fetal liver. We hypothesized UV glucose concentration to be a major regulator of the distribution of glucose supply between the fetal liver and DV, and explored the influence of maternal metabolic status on this distribution. We included 124 healthy women with normal singleton pregnancies, scheduled for elective cesarean section. UV and DV blood flow measurements were performed by Doppler ultrasound immediately before, and blood samples were obtained during surgery. UV blood flow was significantly correlated with DV blood flow, liver blood flow, and the DV shunting fraction, while UV glucose concentration was not. For normal‐weight mothers, the maternal‐fetal glucose gradient was positively correlated with DV shunting fraction, and negatively with liver blood flow. For the fetuses of the overweight mothers no such correlation was found. This indicates that within the normal physiological range the human fetus makes adaptations of blood flow to ensure individual needs related to the offered maternal energy supply.

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Rethinking the role of the brain in glucose homeostasis and diabetes pathogenesis

Cited by 26 publications

References 22 publications

Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission

Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission

Brain control of blood glucose levels: implications for the pathogenesis of type 2 diabetes

The impact of umbilical vein blood flow and glucose concentration on blood flow distribution to the fetal liver and systemic organs in healthy pregnancies

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