A Unified Pathophysiological Construct of Diabetes and its Complications

Schwartz, Stanley; Epstein, Solomon; Corkey, Barbara E.; Grant, Struan F.A.; Gavin, James R.; Aguilar, Richard; Herman, Mary E.

doi:10.1016/j.tem.2017.05.005

Cited by 85 publications

(123 citation statements)

References 56 publications

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“…We therefore ensured that urolithin C retains some efficiency in enhancing glucose‐induced insulin secretion in INS‐1 cells exposed to high glucose concentration, a cellular model used to mirror the deterioration of beta cell function due to glucotoxicity (Quinault et al, ). For the same purpose, the antioxidant activity of urolithin C may constitute an additional asset since beta cells and other cell types implicated in diabetes‐related complications are particularly vulnerable to oxidative stress, stemming from metabolic dysregulation (Schwartz et al, ). The multi‐target nature of urolithins as well as their effect on Ca 2+ signalling, at least for urolithin C, may possibly raise some concerns regarding their low selectivity and potential toxicity and thus constitute a drawback for their use in vivo.…”

Section: Discussionmentioning

confidence: 99%

The ellagitannin metabolite urolithin C is a glucose‐dependent regulator of insulin secretion through activation of L‐type calcium channels

Bayle

Neasta

Dall’Asta

et al. 2019

British J Pharmacology

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Background and Purpose The pharmacology of polyphenol metabolites on beta‐cell function is largely undetermined. We sought to identify polyphenol metabolites that enhance the insulin‐secreting function of beta‐cells and to explore the underlying mechanisms. Experimental Approach INS‐1 beta‐cells and rat isolated islets of Langerhans or perfused pancreas preparations were used for insulin secretion experiments. Molecular modelling, intracellular Ca2+ monitoring, and whole‐cell patch‐clamp recordings were used for mechanistic studies. Key Results Among a set of polyphenol metabolites, we found that exposure of INS‐1 beta‐cells to urolithins A and C enhanced glucose‐stimulated insulin secretion. We further characterized the activity of urolithin C and its pharmacological mechanism. Urolithin C glucose‐dependently enhanced insulin secretion in isolated islets of Langerhans and perfused pancreas preparations. In the latter, enhancement was reversible when glucose was lowered from a stimulating to a non‐stimulating concentration. Molecular modelling suggested that urolithin C could dock into the Cav1.2 L‐type Ca2+ channel. Calcium monitoring indicated that urolithin C had no effect on basal intracellular Ca2+ but enhanced depolarization‐induced increase in intracellular Ca2+ in INS‐1 cells and dispersed cells isolated from islets. Electrophysiology studies indicated that urolithin C dose‐dependently enhanced the L‐type Ca2+ current for levels of depolarization above threshold and shifted its voltage‐dependent activation towards more negative potentials in INS‐1 cells. Conclusion and Implications Urolithin C is a glucose‐dependent activator of insulin secretion acting by facilitating L‐type Ca2+ channel opening and Ca2+ influx into pancreatic beta‐cells. Our work paves the way for the design of polyphenol metabolite‐inspired compounds aimed at ameliorating beta‐cell function.

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Section: Discussionmentioning

confidence: 99%

The ellagitannin metabolite urolithin C is a glucose‐dependent regulator of insulin secretion through activation of L‐type calcium channels

Bayle

Neasta

Dall’Asta

et al. 2019

British J Pharmacology

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“…Diabetes mellitus is a world-wide, growing epidemic with an estimated 415 million adults globally, including 30 million Americans (∼9% of the US population), living with diabetes (1)(2)(3)(4). Patients with diabetes are at increased risk of death and a myriad of serious diabetes-specific complications (neuropathy, nephropathy, retinopathy) and other associated complications or conditions with overlapping pathophysiologies (cardiovascular disease, dementia, psoriasis, non-alcoholic steatohepatitis, metabolic syndrome, and cancer (5,6). Diabetic retinopathy is one of the most common diabetes-specific complications with an estimated global prevalence of 382 million (5,7).…”

Section: Introductionmentioning

confidence: 99%

“…Risk factors that actually cause hyperglycemia appear to be the same factors that raise the risk for retinopathy, impacting the neuronal tissue as well as causing microvascular injury. Indeed, retinopathy may be best understood in the context of a unified pathophysiologic construct of diabetes and its complications (6). This construct submits that the same pathophysiologic processes that cause injury to the pancreatic β-cell are responsible for the diabetes-specific complications of diabetes in other tissues as well as other conditions with overlapping pathophysiologies (6).…”

Section: Introductionmentioning

confidence: 99%

Diabetic Retinopathy–An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes

Sinclair

Schwartz

2019

Front. Endocrinol.

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Diabetes mellitus is a world-wide epidemic and diabetic retinopathy, a devastating, vision-threatening condition, is one of the most common diabetes-specific complications. Diabetic retinopathy is now recognized to be an inflammatory, neuro-vascular complication with neuronal injury/dysfunction preceding clinical microvascular damage. Importantly, the same pathophysiologic mechanisms that damage the pancreatic β-cell (e.g., inflammation, epigenetic changes, insulin resistance, fuel excess, and abnormal metabolic environment), also lead to cell and tissue damage causing organ dysfunction, elevating the risk of all complications, including diabetic retinopathy. Viewing diabetic retinopathy within the context whereby diabetes and all its complications arise from common pathophysiologic factors allows for the consideration of a wider array of potential ocular as well as systemic treatments for this common and devastating complication. Moreover, it also raises the importance of the need for methods that will provide more timely detection and prediction of the course in order to address early damage to the neurovascular unit prior to the clinical observation of microangiopathy. Currently, treatment success is limited as it is often initiated far too late and after significant neurodegeneration has occurred. This forward-thinking approach of earlier detection and treatment with a wider array of possible therapies broadens the physician's armamentarium and increases the opportunity for prevention and early treatment of diabetic retinopathy with preservation of good vision, as well the prevention of similar destructive processes occurring among other organs.

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“…They also emphasise the concept of epigenetics and inflammation, as well as the role of inflammation and immune dysregulation, in the pathophysiology of T2DM [44]. They suggest how data from “multiomics” could be integrated with electronic medical records to provide “dynamic decision support” for recommendations regarding the treatment of T2DM.…”

Section: Precision Diabetes In T2dmmentioning

confidence: 99%

“…Figure 1 summarises the concept of a futuristic model of precision diabetes which could be applied at a diabetes clinic to offer personalised diabetes care [44]. …”

Section: Precision Diabetes In T2dmmentioning

confidence: 99%

Precision Diabetes Is Slowly Becoming a Reality

Mohan

Radha

2019

Med Princ Pract

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The concept of precision medicine is becoming increasingly popular. The use of big data, genomics and other “omics” like metabolomics, proteomics and transcriptomics could make the dream of personalised medicine become a reality in the near future. As far as polygenic forms of diabetes like type 2 and type 1 diabetes are concerned, interesting leads are emerging, but precision diabetes is still in its infancy. However, with regard to monogenic forms of diabetes like maturity-onset diabetes of the young and neonatal diabetes mellitus, rapid strides have been made and precision diabetes has already become part of the clinical tools used at advanced diabetes centres. In patients with some monogenic form of diabetes, if the appropriate gene defects are identified, insulin injections can be stopped and be replaced by oral sulphonylurea drugs. In the coming years, rapid advances can be expected in the field of precision diabetes, thereby making the control of diabetes more effective and hopefully leading to prevention of its complications and improvement of the quality of life of people afflicted with diabetes.

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A Unified Pathophysiological Construct of Diabetes and its Complications

Cited by 85 publications

References 56 publications

The ellagitannin metabolite urolithin C is a glucose‐dependent regulator of insulin secretion through activation of L‐type calcium channels

The ellagitannin metabolite urolithin C is a glucose‐dependent regulator of insulin secretion through activation of L‐type calcium channels

Diabetic Retinopathy–An Underdiagnosed and Undertreated Inflammatory, Neuro-Vascular Complication of Diabetes

Precision Diabetes Is Slowly Becoming a Reality

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