Genetic activation of α-cell glucokinase in mice causes enhanced glucose-suppression of glucagon secretion during normal and diabetic states

Bahl, Varun; May, Catherine Lee; Perez, Alanis; Gläser, Benjamin; Kaestner, Klaus H.

doi:10.1016/j.molmet.2021.101193

Cited by 29 publications

(31 citation statements)

References 34 publications

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“…debate has centered on the question of whether glucose suppression of glucagon secretion is mediated via intrinsic, paracrine, or autonomic mechanisms (Gylfe, 2016), although it seems likely that a cells (like b cells) adeptly integrate multiple signals for precise physiologic control of glucagon. A role for direct glucose sensing is supported by the ability of glucose to modulate a cell ATP-sensitive K + channels (Zhang et al, 2013), the impact of a cell glucokinase manipulation on in vitro cell function, and in vivo glucagon secretion and glucose homeostasis (Moede et al, 2020;Bahl et al, 2021;Basco et al, 2018). Here, we show that glucose suppresses human and mouse a cell exocytosis, consistent with a recent report where exocytosis was measured by live-cell imaging (Omar-Hmeadi et al, 2020).…”

Section: Discussionsupporting

confidence: 90%

Heterogenous impairment of α cell function in type 2 diabetes is linked to cell maturation state

Dai¹,

Camunas-Soler²,

Briant³

et al. 2022

Cell Metabolism

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Section: Discussionsupporting

confidence: 90%

Heterogenous impairment of α cell function in type 2 diabetes is linked to cell maturation state

Dai¹,

Camunas-Soler²,

Briant³

et al. 2022

Cell Metabolism

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“…Thus, targeting of the pancreatic α cell and its main secretory product glucagon has potential as a treatment for diabetes ( 6 ). Glucagon secretion from α cells is affected by paracrine modulators such as intra-islet insulin ( 12 ), zinc ( 13 ), somatostatin secreted from δ cells ( 14 ), cAMP ( 15 ) and cAMP-activated ion channels ( 16 ), Ca 2+ ( 17 ), cytokine effects ( 18 ), gap junctions ( 19 ), direct effects of glucose ( 14 , 20 ), and GABA ( 21 ). Both β and α cells express ATP-sensitive K + channels (K ATP ) and together with the glucose-sensing enzyme glucokinase play an essential role in the regulation of insulin and glucagon secretion.…”

Section: Introductionmentioning

confidence: 99%

α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody–positive individuals

Doliba¹,

Rozo²,

Roman³

et al. 2022

Journal of Clinical Investigation

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BACKGROUND Multiple islet autoantibodies (AAbs) predict the development of type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in only approximately 15% of individuals who are positive for single AAbs (generally against glutamic acid decarboxylase [GADA]); hence, the single GADA + state may represent an early stage of T1D. METHODS Here, we functionally, histologically, and molecularly phenotyped human islets from nondiabetic GADA + and T1D donors. RESULTS Similar to the few remaining β cells in the T1D islets, GADA + donor islets demonstrated a preserved insulin secretory response. By contrast, α cell glucagon secretion was dysregulated in both GADA + and T1D islets, with impaired glucose suppression of glucagon secretion. Single-cell RNA-Seq of GADA + α cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of cAMP-dependent protein kinase inhibitor β ( PKIB ), providing a molecular basis for the loss of glucose suppression and the increased effect of 3-isobutyl-1-methylxanthine (IBMX) observed in GADA + donor islets. CONCLUSION We found that α cell dysfunction was present during the early stages of islet autoimmunity at a time when β cell mass was still normal, raising important questions about the role of early α cell dysfunction in the progression of T1D. FUNDING This work was supported by grants from the NIH (3UC4DK112217-01S1, U01DK123594-02, UC4DK112217, UC4DK112232, U01DK123716, and P30 DK019525) and the Vanderbilt Diabetes Research and Training Center (DK20593).

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“…Remarkably, the entire set of glycolysis genes, from GCK to PDH is downregulated in alpha cells from GADA+ donors. It was recently demonstrated that the rate of glycolytic flux via glucokinase and thus ATP production determines the setpoint for inhibition of glucagon secretion by glucose (Bahl et al, 2021; Basco et al, 2018; Moede et al, 2020). Therefore, if GADA+ alpha cells produce ATP from glucose less efficiently because of lower glycolytic flux and oxidative phosphorylation, then a given concentration of glucose would less efficiently suppress glucagon secretion, providing a possible molecular explanation for the physiological observations shown in Figure 2.…”

Section: Resultsmentioning

confidence: 99%

“…Glucagon secretion from alpha cells is impacted by cAMP (Yu et al, 2019) and Ca 2+ (Vieira et al, 2007), as well as intra-islet insulin (Xu et al, 2006), GABA (Kittler and Moss, 2003; Xu et al, 2006), cAMP-activated ion channels (Huang et al, 2017), and gap junctions (Dufer, 2018). A direct role for glucose sensing via glucokinase in alpha cells has also been identified as a key factor in glucose inhibition of glucagon secretion (Bahl et al, 2021; Basco et al, 2018; Moede et al, 2020). In addition, glucagon released from alpha cells acts in a paracrine fashion on beta cells, with this crosstalk important for high efficiency glucose stimulation of insulin secretion (Sharma et al, 2018; Svendsen et al, 2018; Zhu et al, 2019b).…”

Section: Introductionmentioning

confidence: 99%

Alpha cell dysfunction in early type 1 diabetes

Doliba

Rozo

Roman

et al. 2021

Preprint

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Multiple islet autoantibodies (AAb) predict type 1 diabetes (T1D) and hyperglycemia within 10 years. By contrast, T1D develops in just ~15% of single AAb+ (generally against glutamic acid decarboxylase, GADA+) individuals; hence the single GADA+ state may represent an early stage of T1D amenable to interventions. Here, we functionally, histologically, and molecularly phenotype human islets from non-diabetic, GADA+ and T1D donors. Similar to the few remaining beta cells in T1D islets, GADA+ donor islets demonstrated a preserved insulin secretory response. By contrast, alpha cell glucagon secretion was dysregulated in both T1D and GADA+ islets with impaired glucose suppression of glucagon secretion. Single cell RNA sequencing (scRNASeq) of GADA+ alpha cells revealed distinct abnormalities in glycolysis and oxidative phosphorylation pathways and a marked downregulation of PKIB, providing a molecular basis for the loss of glucose suppression and the increased effect of IBMX observed in GADA+ donor islets. The striking observation of a distinct early defect in alpha cell function that precedes beta cell loss in T1D suggests that not only overt disease, but also the progression to T1D itself, is bihormonal in nature.

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Genetic activation of α-cell glucokinase in mice causes enhanced glucose-suppression of glucagon secretion during normal and diabetic states

Cited by 29 publications

References 34 publications

Heterogenous impairment of α cell function in type 2 diabetes is linked to cell maturation state

Heterogenous impairment of α cell function in type 2 diabetes is linked to cell maturation state

α Cell dysfunction in islets from nondiabetic, glutamic acid decarboxylase autoantibody–positive individuals

Alpha cell dysfunction in early type 1 diabetes

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