Preferential Gq signaling in diabetes: an electrical switch in incretin action and in diabetes progression?

Nichols, Colin G.; York, Nathaniel W.; Remedi, Marı́a S.

doi:10.1172/jci143199

Cited by 8 publications

(12 citation statements)

References 22 publications

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“…Moreover, these findings help explain why an increase in fasting plasma glucose concentration that is still within the normal range (<100 mg/dL) is associated with an increase in the risk of developing T2D (17)(18)(19). The mechanism(s) responsible for the increase in insulin secretion caused by obesity are unclear, but likely involve an increase in both β-cell number (20), (21) and function of individual β-cells (22,23), which together increase the insulin secretory response to a glucose stimulus.…”

Section: Discussionmentioning

confidence: 95%

“…The mechanism or mechanisms responsible for the increase in insulin secretion caused by obesity are unclear, but probably involve an increase in both β cell numbers ( 20 , 21 ) and the function of individual β cells ( 22 , 23 ), which together increase the insulin secretory response to a glucose stimulus. The increase in β cell mass associated with obesity is presumably caused by chronic stimulation of pancreatic islets by insulinogenic nutrients and growth factors ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

“…The increase in β cell mass associated with obesity is presumably caused by chronic stimulation of pancreatic islets by insulinogenic nutrients and growth factors ( 21 ). Obesity is also associated with a decrease in β cell K ATP channel density, which enhances cellular excitability and GSIS ( 22 , 23 ). Impaired GSIS is presumably caused by both a reduction in β cell mass ( 20 , 24 ) and individual β cell function ( 22 ).…”

Section: Discussionmentioning

confidence: 99%

“…Obesity is also associated with a decrease in β cell K ATP channel density, which enhances cellular excitability and GSIS ( 22 , 23 ). Impaired GSIS is presumably caused by both a reduction in β cell mass ( 20 , 24 ) and individual β cell function ( 22 ). In addition, differences in the incretin response or incretin sensitivity could also be involved in causing differences in the β cell response to glucose ingestion among groups ( 25 , 26 ).…”

Section: Discussionmentioning

confidence: 99%

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β Cell function and plasma insulin clearance in people with obesity and different glycemic status

Mittendorfer¹,

Patterson²,

Smith³

et al. 2022

Journal of Clinical Investigation

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Background: It is unclear how excess adiposity and insulin resistance affect β-cell function, insulin secretion, and insulin clearance in people with obesity. Methods:We used a hyperinsulinemic-euglycemic clamp procedure and a modified oral glucose tolerance test to evaluate the interrelationships among obesity, insulin sensitivity, insulin kinetics, and glycemic status in five groups: normoglycemic lean and obese with: i) normal fasting glucose and normal glucose tolerance (Ob-NFG-NGT), ii) NFG and impaired glucose tolerance (Ob-NFG-IGT), iii) impaired fasting glucose and IGT (Ob-IFG-IGT), and iv) type 2 diabetes (Ob-T2D).Results: Glucose-stimulated insulin secretion (GSIS), an assessment of β-cell function, was greater in the Ob-NFG-NGT and Ob-NFG-IGT groups than in the lean group, even when insulin sensitivity was matched in the obese and lean groups. Insulin sensitivity, not GSIS, was decreased in the Ob-NFG-IGT group compared with the Ob-NFG-NGT group, whereas GSIS, not insulin sensitivity, was decreased in the Ob-IFG-IGT and Ob-T2D groups compared with the Ob-NFG-NGT and Ob-NFG-IGT groups. Insulin clearance was directly related to insulin sensitivity and inversely related to the postprandial increase in insulin secretion and plasma insulin concentration. Conclusion.Increased adiposity per se, not insulin resistance, enhances insulin secretion in people with obesity. The obesity-induced increase in insulin secretion, in conjunction with a decrease in insulin clearance, sufficiently raise plasma insulin concentrations needed to maintain normoglycemia in people with moderate, but not severe insulin resistance. A deterioration in β-cell function, not a decrease in insulin sensitivity, is a determinant of IFG and ultimately leads to T2D.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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β Cell function and plasma insulin clearance in people with obesity and different glycemic status

Mittendorfer¹,

Patterson²,

Smith³

et al. 2022

Journal of Clinical Investigation

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“…Based on rodent models, it has recently been suggested that the reason for the abolished insulinotropic effect of GIP, and not GLP‐1, is a shift in G protein recruitment from Gs to Gq 112 . The GLP‐1 receptor is able to recruit Gq to provide the downstream signalling that results in insulin secretion, whereas the GIP receptor is not 113 . Whether this shift in G protein recruitment is involved in the actions of tirzepatide on beta cells has yet to be confirmed 50 …”

Section: Clinical Data On Unimolecular Dual Incretin Receptor Agonistsmentioning

confidence: 99%

The importance of glucose‐dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide

Gasbjerg

Meier

Holst

et al. 2023

Diabetes Obesity Metabolism

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Tirzepatide is a unimolecular co‐agonist of the glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor‐activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP‐1 and GIP, their receptors, and previous results of co‐targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP‐1 and GIP receptor activation, tirzepatide does not seem to have a classical co‐activating mode of action in humans. Rather, in vitro studies of the human GLP‐1 and GIP receptors reveal a biased GLP‐1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.

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Worksite-based intensive lifestyle therapy has profound cardiometabolic benefits in people with obesity and type 2 diabetes

Yoshino

Smith

et al. 2022

Cell Metabolism

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Preferential Gq signaling in diabetes: an electrical switch in incretin action and in diabetes progression?

Abstract: Switching G protein signaling in hyperexcited β cells 6 2 3 7 jci.org Volume 130 Number 12

Cited by 8 publications

References 22 publications

β Cell function and plasma insulin clearance in people with obesity and different glycemic status

β Cell function and plasma insulin clearance in people with obesity and different glycemic status

The importance of glucose‐dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide

Worksite-based intensive lifestyle therapy has profound cardiometabolic benefits in people with obesity and type 2 diabetes

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