The β-cell glucose toxicity hypothesis: Attractive but difficult to prove

Weir, Gordon C.; Butler, Peter C.; Bonner-Weir, Susan

doi:10.1016/j.metabol.2021.154870

Cited by 21 publications

(15 citation statements)

References 107 publications

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“… 22 Islet function in the hyperglycemia environment of diabetes reduced markedly and was reversible if glucose returned to normal. 23 Therefore, we speculate that oxidative stress and decreased levels of insulin and C-peptide are caused by glucose toxicity. We also found that the CEA levels were higher in diabetic inpatients with BMI < 24 kg/m2 than in overweight or obesity patients.…”

Section: Discussionmentioning

confidence: 95%

High Prevalence of Abnormal Carcinoembryonic Antigen in Diabetic Inpatients with Poor Glycemic Control

Liu¹,

Jaturapitakkul²,

Zhou³

2022

DMSO

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Introduction Higher serum carcinoembryonic antigen (CEA) was found in diabetic patients rather than controls. However, the prevalence of abnormal CEA among diabetic inpatients with a large proportion of poor glycemic control is unclear. Methods A total of 385 diabetic inpatients were included in this study. We collected information from a large clinical database. Patients with malignant tumors were excluded by examination and follow-up. Results We found a surprisingly high prevalence (14.3%) of diabetic inpatients with CEA above normal. The proportion of patients with abnormal CEA was significantly different in subgroups with different blood glucose levels, 20.4% in the HbA1c ≥ 9% group, and 8.5% in the HbA1c < 9%, p = 0.000. We found that the CEA levels were correlated with age, body mass index and HbA1c. The regression coefficient of HbA1c was the highest, B = 0.284, p = 0.000. We also found that the CEA levels were higher in diabetic inpatients with BMI < 24 kg/m2 than the overweight or obesity patients. There was a significant difference in the insulin level and C peptide level between the elevated CEA group and the non-elevated CEA group. Conclusion The elevation of CEA is common in diabetic inpatients, especially those with poor hyperglycemia controlled (HbA1c ≥ 9%). The underlying mechanism may be related to glucose toxicity.

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Section: Discussionmentioning

confidence: 95%

High Prevalence of Abnormal Carcinoembryonic Antigen in Diabetic Inpatients with Poor Glycemic Control

Liu¹,

Jaturapitakkul²,

Zhou³

2022

DMSO

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“…Taken together, we hypothesize that the interaction between FPG and attenuated S i starts to operate around this level of glucose, 5.2 to 5.3 mmol/L, leading to accelerated worsening of glucose metabolism. The possibility of so-called glucose toxicity taking place at around this low level of glucose was recently hypothesized by Weir et al [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Hepatic Steatosis and High-Normal Fasting Glucose as Risk Factors for Incident Prediabetes

Aizawa

Nakasone

Murai

et al. 2022

Journal of the Endocrine Society

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Objective To clarify the impact of hepatic steatosis (HS) indexed by Fatty Liver Index (FLI) and high normal fasting plasma glucose (FPG) as risk factors for incident prediabetes in a non-obese cohort. Methods Data from 1,125 participants with ADA-defined normal glucose metabolism (NGM) (median age and BMI, 52 years and 23.1 kg/m 2, respectively) were used for retrospective analysis. In the entire population, correlation between normal FPG and FLI was evaluated by multiple regression with adjustment for age and sex. Follow-up data from 599 participants in whom 75 g OGTT was repeated 3.7 years later showed that 169 developed prediabetes. This was analyzed by the multivariate Cox proportional hazards model. Results In the entire population, FLI was positively correlated with FPG (P <0.01): mean FLI increased from 15.8 at FPG 4.2 mmol/L to 31.6 at FPG 5.5 mmol/L. Analysis of the 599 participants (2,061 person-years) by Cox model, adjusted for sex, age, family history of diabetes, ISIMATSUDA and Stumvoll-1, clarified an increased risk of prediabetes with high normal FPG and FLI. In in participants with FLI≥16.5, as compared with FLI <16.5, P<0.001. The risk was also increased (2.1 times) in participants with FPG ≥5.3 mmol/L, P<0.001. The cutoff values (unadjusted) were obtained by ROC at the point of the largest Youden’s index using the entire range of the variables. Conclusions Even among non-obese individuals, HS indexed by FLI and a high-normal FPG (≥5.3 mmol/L) are risk factors for prediabetes, independently from insulin.

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“…This impressive homeostasis occurs despite large differences in insulin sensitivity and insulin secretion. Remarkably, insulin sensitivity can vary more that 10-fold (2). Although insulin sensitivity is of obvious importance, its countless intertwined components have proved difficult to dissect.…”

Section: Interplay Between Insulin Secretion and Insulin Sensitivitymentioning

confidence: 99%

Induction of remission in diabetes by lowering blood glucose

Weir

Bonner-Weir

2023

Front. Endocrinol.

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As diabetes continues to grow as major health problem, there has been great progress in understanding the important role of pancreatic beta-cells in its pathogenesis. Diabetes develops when the normal interplay between insulin secretion and the insulin sensitivity of target tissues is disrupted. With type 2 diabetes (T2D), glucose levels start to rise when beta-cells are unable to meet the demands of insulin resistance. For type 1 diabetes (T1D) glucose levels rise as beta-cells are killed off by autoimmunity. In both cases the increased glucose levels have a toxic effect on beta-cells. This process, called glucose toxicity, has a major inhibitory effect on insulin secretion. This beta-cell dysfunction can be reversed by therapies that reduce glucose levels. Thus, it is becoming increasingly apparent that an opportunity exists to produce a complete or partial remission for T2D, both of which will provide health benefit.

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The β-cell glucose toxicity hypothesis: Attractive but difficult to prove

Cited by 21 publications

References 107 publications

High Prevalence of Abnormal Carcinoembryonic Antigen in Diabetic Inpatients with Poor Glycemic Control

High Prevalence of Abnormal Carcinoembryonic Antigen in Diabetic Inpatients with Poor Glycemic Control

Hepatic Steatosis and High-Normal Fasting Glucose as Risk Factors for Incident Prediabetes

Induction of remission in diabetes by lowering blood glucose

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