C-peptide enhances glucagon secretion in response to hyperinsulinemia under euglycemic and hypoglycemic conditions

Moore, Mary Courtney; Warner, Shana O.; Dai, Yufei; Sheanon, Nicole; Smith, Marta S.; Farmer, Ben; Cason, Rebecca L.; Cherrington, Alan D.; Winnick, Jason J.

doi:10.1172/jci.insight.148997

Cited by 4 publications

(2 citation statements)

References 79 publications

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“…Continued secretion of insulin into the portal vein, even the small amount seen in type 1 diabetes, likely attenuates highs through reduction of hepatic glucose production, with increased glucagon response lessening hypoglycaemia. The mechanisms explaining the enhanced glucagon response observed in those with high C‐peptide is unclear, with theories including the suppression of functional β‐cells activating neighbouring α‐cells within intact islets 25 or the presence of C‐peptide itself enhancing the counter regularity responses to hypoglycaemia 26 . This may lower GV and protect against nocturnal dysglycaemia, potentially giving individuals confidence to adhere to more intensive insulin regimens, lowering nocturnal mean glucose.…”

Section: Discussionmentioning

confidence: 99%

Capturing the real‐world benefit of residual β‐cell function during clinically important time‐periods in established Type 1 diabetes

et al. 2022

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Aims Many individuals with type 1 diabetes retain residual β‐cell function, with increased endogenous insulin secretion associated with reduced hyperglycaemia, hypoglycaemia and glycaemic variability. However, it is unknown when these improvements occur during the day. Dysglycaemia is common in overnight and postprandial periods and associated with diabetes complications. Therefore, this study aimed to determine the influence of residual β‐cell function upon nocturnal and postprandial glycaemic control in established type 1 diabetes. Methods Under free‐living conditions, 66 participants wore a blinded continuous glucose monitor (CGM), kept a food diary, and completed a stimulated urine C‐peptide creatinine (UCPCR) test. Nocturnal, and postprandial CGM outcomes (participant means and discrete event analysis) were compared between UCPCR groups: undetectable (Cpepund), low (Cpeplow: 0.001–0.19 nmol/mmol) and high (Cpephigh: ≥0.2 nmol/mmol). Results Greater β‐cell function was associated with incremental improvements in glycaemia. Cpephigh spent significantly greater time in normoglycaemia than Cpepund overnight (76 ± 20% vs. 58 ± 20%, p = 0.005) and 0–300 mins postprandially (68 ± 22% vs. 51 ± 22%, p = 0.045), while also having reducing nocturnal variability (SD 1.12 ± 0.41 vs. 1.52 ± 0.43 mmol/L, p = 0.010). Analysis of individual events, controlling for diabetes duration, BMI, basal insulin, use of a continuous or flash glucose monitor and (for postprandial) meal type, carbohydrate and bolus insulin intake, replicated the group findings, additionally demonstrating Cpepund had increased hyperglycaemia versus Cpeplow overnight and increased postprandial hypoglycaemic events compared with Cpephigh. For all participants, breakfast had a significantly higher incremental area under the curve than lunch and dinner. Conclusions Residual β‐cell function is associated with improved nocturnal and postprandial glycaemic control. These data may be of clinical importance for identifying specific periods and individuals where further glycaemic management strategies would be beneficial.

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Section: Discussionmentioning

confidence: 99%

Capturing the real‐world benefit of residual β‐cell function during clinically important time‐periods in established Type 1 diabetes

et al. 2022

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“…Moore et al. ( 101 ) explored the role of C-peptide in insulin-induced hypoglycemia by testing the effects of C-peptide infusion on glucagon secretion under isoglycemic and hypoglycemic conditions in dogs (5 males/4 females). In the experiments, glucagon secretion remained unchanged in the isoglycemic-hyperinsulinemic response in the C-peptide infusion group, whereas it increased twofold during hypoglycemia.…”

Section: C-peptide and Diabetic Emergenciesmentioning

confidence: 99%

The role of C-peptide in diabetes and its complications: an updated review

Chen,

Huang,

Liu

et al. 2023

Front. Endocrinol.

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Worldwide, diabetes and its complications have seriously affected people’s quality of life and become a serious public health problem. C-peptide is not only an indicator of pancreatic β-cell function, but also a biologically active peptide that can bind to cell membrane surface signaling molecules and activate downstream signaling pathways to play antioxidant, anti-apoptotic and inflammatory roles, or regulate cellular transcription through internalization. It is complex how C-peptide is related to diabetic complications. Both deficiencies and overproduction can lead to complications, but their mechanisms of action may be different. C-peptide replacement therapy has shown beneficial effects on diabetic complications in animal models when C-peptide is deficient, but results from clinical trials have been unsatisfactory. The complex pattern of the relationship between C-peptide and diabetic chronic complications has not yet been fully understood. Future basic and clinical studies of C-peptide replacement therapies will need to focus on baseline levels of C-peptide in addition to more attention also needs to be paid to post-treatment C-peptide levels to explore the optimal range of fasting C-peptide and postprandial C-peptide maintenance.

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A physiologic increase in brain glucagon action alters the hepatic gluconeogenic/glycogenolytic ratio but not glucagon’s overall effect on glucose production

Edgerton

Kraft

Smith

et al. 2023

American Journal of Physiology-Endocrinology and Metabolism

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It has been proposed that brain glucagon action inhibits glucagon stimulated hepatic glucose production (HGP), which may explain, at least in part, why glucagon's effect on HGP is transient. Pharmacologic off-target effects of glucagon in the brain may have been responsible for previously observed effects, however. Therefore, the aim of this study was to determine if central glucagon action plays a physiologic role in the regulation of HGP. Insulin was maintained at baseline while glucagon was either infused into the carotid and vertebral arteries or into a peripheral (leg) vein at rates designed to increase glucagon in the head in one group, while keeping glucagon at the liver matched between groups. The extraction rate of glucagon across the head was high (double that of the liver), and hypothalamic cAMP increased 2-fold, in proportion to the exposure of the brain to increased glucagon, but HGP was not reduced by the increase in brain glucagon signaling, as had been suggested previously (the AUCs for HGP were 840±14 vs 871±36 mg/kg/240 min in head vs peripheral infusion groups, respectively). CNS glucagon action reduced circulating free fatty acids and glycerol, and this was associated with a modest reduction in net hepatic gluconeogenic flux. Offsetting autoregulation by the liver (i.e. a reciprocal increase in net hepatic glycogenolysis) prevented a change in HGP, however. Thus, while physiologic engagement of the brain by glucagon can alter hepatic carbon flux it does not appear to be responsible for the transient fall in HGP that occurs following the stimulation of HGP during a square wave rise in glucagon.

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C-peptide enhances glucagon secretion in response to hyperinsulinemia under euglycemic and hypoglycemic conditions

Cited by 4 publications

References 79 publications

Capturing the real‐world benefit of residual β‐cell function during clinically important time‐periods in established Type 1 diabetes

Capturing the real‐world benefit of residual β‐cell function during clinically important time‐periods in established Type 1 diabetes

The role of C-peptide in diabetes and its complications: an updated review

A physiologic increase in brain glucagon action alters the hepatic gluconeogenic/glycogenolytic ratio but not glucagon’s overall effect on glucose production

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