Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study

Bizzotto, Roberto; Jennison, Christopher; Jones, Angus G.; Kurbasic, Azra; Tura, Andrea; Kennedy, Gwen; Bell, Jimmy D.; Thomas, E. Louise; Frost, Gary; Eriksen, Rebeca; Koivula, Robert W.; Brage, Sören; Kaye, Jane; Hattersley, Andrew T.; Heggie, Alison; McEvoy, Donna; Hart, Leen M. ‘t; Beulens, Joline W.J.; Elders, Petra; Musholt, Petra B.; Ridderstråle, Martin; Hansen, Tue H.; Allin, Kristine H.; Hansen, Torben; Vestergaard, Henrik; Lundgaard, Agnete T.; Thomsen, Henrik S.; Masi, Federico De; Tsirigos, Konstantinos D.; Brunak, Søren; Viñuela, Ana; Mahajan, Anubha; McDonald, Timothy J.; Kokkola, Tarja; Forgie, Ian; Giordano, G; Ruetten, Hartmut; Dermitzakis, Emmanouil T.; McCarthy, Mark; Pedersen, Oluf; Schwenk, Jochen M.; Adamski, Jerzy; Franks, Paul W.; Walker, Mark; Pearson, Ewan R.; Mari, Andrea; Abdalla, Moustafa; Adam, Jonathan; Adragni, Kofi; Allesøe, Rosa Lundbye; Arumugam, Muthu; Pasdar, Naeimeh Atabaki; Baltauss, Tania; Banasik, Karina; Baum, Patrick; Bergstrom, Margit; Bianzano, Susanna; Bonneford, Amelie; Brorsson, Caroline; Brown, Andrew A.; Cabrelli, Louise; Caïazzo, Robert; Canouil, Mickaël; Dale, Matilda; Davtian, David; Dawed, Adem Y; Préville, Nathalie de; Dekkers, Koen F.; Deshmukh, Harshal; Dings, Christiane; Donnelly, Louise A.; Dutta, Avirup; Ehrhardt, Beate; Engelbrechtsen, Line; Fernández, Juan Carlos Delgado; Ferrer, J.; Fitipaldi, Hugo; Forman, Annemette; Franks, Paul W.; Frau, Francesca; Fritsche, Andreas; Froguel, Philippe; Gassenhuber, Johann; Giordano, Nick; Giorgino, Toni; Gough, Stephen; Graefe‐Mody, Ulrike; Grallert, Harald; Grempler, Rolf; Groeneveld, Lenka; Groop, Leif; Guðmundsdóttir, Valborg; Haid, Mark; Hansen, Torben; Häussler, Ragna S.; Hennige, Anita M.; Hill, Anita; Holl, Reinhard W.; Hong, Mun‐Gwan; Hudson, Michelle; Jablonka, Bernd; Jiao, Yunlong; Johansen, Joachim; Jonsson, Anna; Karaderi, Tugce; Klintenberg, Maria; Koopman, Anitra D.M.; Kuulasmaa, Teemu; Laakso, Markku; Lehr, Thorsten; Loftus, Heather; Mazzoni, Gianluca; McRobert, Nicky; McVittie, Ian; Mourby, Miranda; Mutie, Pascal M.; Nice, Rachel; Nicolay, Claudia; Nielsen, Agnes; Nilsson, Birgitte; Palmer, Colin N. A.; Pattou, François; Pávó, Imre; Pedersen, Helle; Perry, Mandy H; Pomares-Millan, Hugo; Rasmussen, Simon; Raverdy, Violeta; Robertson, Neil; Roderick, Slieker C.; Rodriquez, Marianne; Rutters, Femke; Sackett, Peter Wad; Scherer, Nina; Shah, N. S.; Sharma, Sapna; Sihinevich, Iryna; Søndertoft, Nadja B; Stærfeldt, Hans‐Henrik; Steckel-Hamann, Birgit; Teare, Harriet; Thomas, Cecilia Engel; Thomas, Melissa K.; Thomas, E. Louise; Thorand, Barbara; Thorne, Claire E.; Tillner, J.; Troll, Martina; Uhlén, Mathias; Leeuwen, Nienke van; Verkindt, Hélène; Vogt, Josef Korbinian; Wake, Dianne; Wesolowska-Andersen, Agata; Whitcher, Brandon; Wu, Han

doi:10.2337/dc20-1567

Cited by 17 publications

(8 citation statements)

References 32 publications

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“…In a paper by Zaharia et al 30 data generated by hyperinsulinemic euglycemic clamp and C‐peptide response to intravenous glucose were included in a similar cluster analysis, confirming with more sophisticated techniques the existence of the subgroups described by Ahlqvist et al. 29 The same clusters were observed by Dennis et al, 31 who used the HOMA for investigating insulin secretion and sensitivity, and by Bizzotto et al 32 who used mathematical models applied to mixed meal tests for the assessment of both insulin secretion and sensitivity.…”

Section: Discussionsupporting

confidence: 56%

Insulin resistance and beta‐cell dysfunction in newly diagnosed type 2 diabetes: Expression, aggregation and predominance. Verona Newly Diagnosed Type 2 Diabetes Study 10

Bonora

Trombetta

Dauriz

et al. 2022

Diabetes Metabolism Res

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Aims:We investigated quantitative expression, mutual aggregation and relation with hyperglycemia of insulin resistance (IR) and beta-cell dysfunction (BCD) in newly diagnosed type 2 diabetes. Methods:We assessed IR with euglycemic hyperinsulinemic clamp and BCD with modelled glucose/C-peptide response to oral glucose in 729 mostly drug-naïve patients. We measured glycated hemoglobin, pre-prandial, post-prandial and mealrelated excursion of blood glucose.

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Section: Discussionsupporting

confidence: 56%

Insulin resistance and beta‐cell dysfunction in newly diagnosed type 2 diabetes: Expression, aggregation and predominance. Verona Newly Diagnosed Type 2 Diabetes Study 10

Bonora

Trombetta

Dauriz

et al. 2022

Diabetes Metabolism Res

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show abstract

“…Due to the fact that changes in blood lipids reflect an immediate/rapid response to a changed environment, the cumulative lipid burden reflects cumulative long-term changes, and our results suggested that the blood lipid levels changed before the occurrence of T2DM. In the study by Bizzotto R et al, 26 they found that the progression rates of TG and HDL were correlated with the progression of HbA1c, which may be due to the accumulation of excessive lipids through visceral fat, thus resulting in insulin resistance or excessive glucose production and subsequently resulting in the deterioration of HbA1c. This suggests that visceral fat may be involved in the progression of diabetes.…”

Section: Discussionmentioning

confidence: 96%

The Role of Changes in Cumulative Lipid Parameter Burden in the Pathogenesis of Type 2 Diabetes Mellitus: A Cohort Study of People Aged 35–65 Years in Rural China

Wang¹,

Xie²,

Zhang³

et al. 2022

DMSO

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Purpose The main purpose of this study was to examine the effect of the cumulative exposure of blood lipid parameters on type 2 diabetes mellitus (T2DM). Another purpose was to explore whether the cumulative burden of blood lipid parameters plays a certain role in the pathogenesis of diet affecting T2DM. Patients and Methods A total of 63 cases of diabetes occurred from 2017 to 2020, with an incidence density of 3.71 person-years. The dietary intake of the residents was obtained by using a dietary frequency questionnaire (FFQ). Cumulative lipid parameter burden was calculated according to the number of years (2016–2020) multiplied by total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL) and triglyceride (TG). A Cox proportional hazard model was used to estimate the effect of cumulative lipid burden on T2DM. A mediating analysis of accelerated failure time (AFT) was used to investigate the mediating effects of certain foods, the cumulative lipid parameter burden and T2DM. Results A higher cumulative TG load corresponded to a higher risk of T2DM onset ( P trend =0.021). After adjusting for covariates, the highest quartile cumulative TG burden had a 3.462 times higher risk of T2DM than that in the lowest quartile ( HR =3.462, 95% CI : 1.297–9.243). Moreover, a higher cumulative HDL load corresponded to a lower risk of T2DM onset ( P trend =0.006). After adjusting for covariates, the risk of T2DM was 0.314-fold lower in the highest quartile of cumulative HDL burden than that in the lowest quartile ( HR =0.314, 95% CI : 0.131–0.753). Cumulative TG burden partially mediated the association between red meat and T2DM. Conclusion The increase in cumulative HDL burden and the decrease in cumulative HDL burden are related to the incidence of T2DM. Cumulative TG burden was shown to play a partial mediating role in the pathogenesis of red meat and diabetes.

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“…Another possible explanation of our results is that reduction in insulin clearance is a robust compensatory mechanism that does not initially fail, unlike beta-cell compensation, whose failure is considered a key event in the development of diabetes. However, after diabetes has developed, increasing clearance would reduce the amount of insulin available to promote cellular glucose uptake, and thereby may be an independent predictor of worsening glycemia over time, as demonstrated in a prospective study of 732 patients with recently diagnosed type 2 diabetes [ 33 ]. This suggests that sequential failure of insulin homeostasis mechanisms contribute to the onset of diabetes (failure of insulin secretion to remain high) and potentially to the progression of diabetes (failure of insulin clearance to remain low).…”

Section: Discussionmentioning

confidence: 99%

Defining the Relative Role of Insulin Clearance in Early Dysglycemia in Relation to Insulin Sensitivity and Insulin Secretion: The Microbiome and Insulin Longitudinal Evaluation Study (MILES)

et al. 2021

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Insulin resistance and insufficient insulin secretion are well-recognized contributors to type 2 diabetes. A potential role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining decreased insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in a cohort of 353 non-Hispanic White and African American individuals recruited in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Regression models examined the individual and joint contributions of these traits to early dysglycemia (prediabetes or newly diagnosed diabetes). In separate models, reduced insulin sensitivity, reduced disposition index, and reduced insulin clearance were associated with dysglycemia. In a joint model, only insulin resistance and reduced insulin secretion were associated with dysglycemia. Models with insulin sensitivity, disposition index, or three insulin traits had the highest discriminative value for dysglycemia (area under the receiver operating characteristics curve of 0.82 to 0.89). These results suggest that in the race groups studied, insulin resistance and compromised insulin secretion are the main independent underlying defects leading to early dysglycemia.

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Processes Underlying Glycemic Deterioration in Type 2 Diabetes: An IMI DIRECT Study

Abstract: The version presented here may differ from the published version. If citing, you are advised to consult the published version for pagination, volume/issue and date of publication Full titleProcesses underlying glycemic deterioration in type 2 diabetes: An IMI DIRECT study

Cited by 17 publications

References 32 publications

Insulin resistance and beta‐cell dysfunction in newly diagnosed type 2 diabetes: Expression, aggregation and predominance. Verona Newly Diagnosed Type 2 Diabetes Study 10

Insulin resistance and beta‐cell dysfunction in newly diagnosed type 2 diabetes: Expression, aggregation and predominance. Verona Newly Diagnosed Type 2 Diabetes Study 10

The Role of Changes in Cumulative Lipid Parameter Burden in the Pathogenesis of Type 2 Diabetes Mellitus: A Cohort Study of People Aged 35–65 Years in Rural China

Defining the Relative Role of Insulin Clearance in Early Dysglycemia in Relation to Insulin Sensitivity and Insulin Secretion: The Microbiome and Insulin Longitudinal Evaluation Study (MILES)

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