Glucose-regulated insulin production in the liver improves glycemic control in type 1 diabetic mice

Zhang, Ting; Dong, H. Henry

doi:10.1016/j.molmet.2014.10.005

Cited by 7 publications

(18 citation statements)

References 54 publications

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“…Multiple investigators have employed transcriptional regulation of hepatic insulin production to better match transgenic insulin production with metabolic demands . Among the variety of promoters used to regulate hepatic transgenic insulin, the most effective have incorporated the stimulatory glucose response element native to the rat liver pyruvate kinase (rL‐PK) promoter . In addition to the rL‐PK stimulatory glucose responsive sequence, our G 3 promoter includes the rat insulin‐like growth factor binding protein‐1 (rIGFBP‐1) basal promoter, which contains an inhibitory insulin response region (IRR) (Figure ) .…”

Section: Discussionmentioning

confidence: 73%

mRNA destabilization improves glycemic responsiveness of transcriptionally regulated hepatic insulin gene therapy in vitro and in vivo

Thulé

Lin

Jia

et al. 2017

The Journal of Gene Medicine

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Section: Discussionmentioning

confidence: 73%

mRNA destabilization improves glycemic responsiveness of transcriptionally regulated hepatic insulin gene therapy in vitro and in vivo

Thulé

Lin

Jia

et al. 2017

The Journal of Gene Medicine

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Section: Discussionmentioning

confidence: 99%

“…Both naturally occurring and engineered hybrid promoters have been used to achieve glucose-responsive expression of Ins following in vivo delivery of gene transfer vectors 24, 25, 26, 27, 28, 29, 30. None of these systems, however, has managed to mimic the quick response to glucose of the Ins promoter, 31 and the slow transcriptional activation of these promoters may result in an inadequate Ins secretory response, with postprandial episodes of hyperglycemia followed by hypoglycemia several hours later.…”

Section: Discussionmentioning

confidence: 99%

“…Some of the previous gene therapy approaches developed to counteract diabetic hyperglycemia relied on the glucose-regulated expression of Ins in surrogate non-β cells to respond to the changes in blood glucose. 24 , 25 , 26 , 27 , 28 , 29 , 30 Both naturally occurring and engineered hybrid promoters have been used to achieve glucose-responsive expression of Ins following in vivo delivery of gene transfer vectors. 24 , 25 , 26 , 27 , 28 , 29 , 30 None of these systems, however, has managed to mimic the quick response to glucose of the Ins promoter, 31 and the slow transcriptional activation of these promoters may result in an inadequate Ins secretory response, with postprandial episodes of hyperglycemia followed by hypoglycemia several hours later.…”

Section: Discussionmentioning

confidence: 99%

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Long-Term Efficacy and Safety of Insulin and Glucokinase Gene Therapy for Diabetes: 8-Year Follow-Up in Dogs

Jaén

Vilà

Elias

et al. 2017

Molecular Therapy - Methods & Clinical Development

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Diabetes is a complex metabolic disease that exposes patients to the deleterious effects of hyperglycemia on various organs. Achievement of normoglycemia with exogenous insulin treatment requires the use of high doses of hormone, which increases the risk of life-threatening hypoglycemic episodes. We developed a gene therapy approach to control diabetic hyperglycemia based on co-expression of the insulin and glucokinase genes in skeletal muscle. Previous studies proved the feasibility of gene delivery to large diabetic animals with adeno-associated viral (AAV) vectors. Here, we report the long-term (∼8 years) follow-up after a single administration of therapeutic vectors to diabetic dogs. Successful, multi-year control of glycemia was achieved without the need of supplementation with exogenous insulin. Metabolic correction was demonstrated through normalization of serum levels of fructosamine, triglycerides, and cholesterol and remarkable improvement in the response to an oral glucose challenge. The persistence of vector genomes and therapeutic transgene expression years after vector delivery was documented in multiple samples from treated muscles, which showed normal morphology. Thus, this study demonstrates the long-term efficacy and safety of insulin and glucokinase gene transfer in large animals and especially the ability of the system to respond to the changes in metabolic needs as animals grow older.

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“…Together, these observations strongly suggest a need for further improvements to 3xGIRE.ALB.Ins1-2xfur. Namely, it would be ideal to increase the degree of glucose-induced insulin transcription [23] while also incorporating mechanism(s) to more quickly reduce insulin levels upon restoration of normoglycemia [24]. Overall, such modifications would greatly enhance the dynamic insulin response to changes in glucose levels, leading to a more effective and safer strategy with greater latitude in dosing.…”

Section: Discussionmentioning

confidence: 99%

Long-term correction of diabetic hyperglycemia through glucose-responsive hepatic insulin production using lentivirus

Am¹,

Hw²,

T³

2017

J Diabetol Endocrinol.

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Type 1 diabetes mellitus (T1DM) is a chronic metabolic disorder resulting from the autoimmune destruction of the insulin-producing β cells of the pancreas. The predominant treatment option requires multiple daily insulin injections to control hyperglycemia, but normal glucose regulation remains elusive. As a result, exogenous insulin therapy delays, but does not prevent, the onset of secondary complications associated with T1DM. Whole pancreas and islet transplantation therapies result in better glucose regulation but are greatly limited by donor shortage and the need for lifelong immunosuppression. Hence, there is clearly a need for alternative, state-of-the-art treatment options.Several gene therapy-based strategies have emerged as promising alternatives to current treatments. One potential strategy is to prevent the autoimmune destruction of β cells by delivering genes capable of modifying the immune system or preventing the apoptosis of native β cells [1,2]. Unfortunately, this strategy relies on the early detection of diabetes, which is difficult given that greater than 80% of an individual's β cells have often already been destroyed Journal of Diabetology and EndocrinologyOriginal research Handorf AM et al., J Diabetol Endocrinol. 2017 AbstractType 1 diabetes mellitus (T1DM) is caused by the autoimmune destruction of the insulin-producing β cells of the pancreas. Insulin gene therapy is a promising strategy capable of overcoming the limitations of current treatments, but to become a viable option, it must provide long-term, glucose-responsive control of insulin production. We have previously achieved glucose-responsivity by incorporating glucose-inducible response elements (GIREs) upstream of a liver-specific insulin expression cassette (3xGIRE.ALB.Ins1-2xfur). In this study, 3xGIRE.ALB.Ins1-2xfur was delivered into streptozotocin-induced diabetic rats using lentivirus, resulting in remission of diabetic hyperglycemia for at least 482 days while restoring rate of weight gain in a dose-dependent fashion. Insulin immunostaining showed abundant insulin production in the liver, and qPCR showed 13-20 lentiviral integrations per cell in the liver of rats treated with high dose lentivirus. Negligible integration was found in the pancreas, kidney, spleen and muscle of LV-treated rats, confirming liver specificity. In vitro, LV.3xGIRE.ALB. Ins1-2xfur produced a 4.5-fold increase in insulin production in high glucose conditions, and in vivo, a 1.7-fold increase in insulin levels was found during an intraperitoneal glucose tolerance test. Unfortunately, limitations in large-scale lentivirus production and use of a tissue-specific promoter prevented treatment of more than one rat per batch of lentivirus. Thus, two of the LV-treated diabetic rats were undertreated, while another two rats were over treated, becoming hypoglycemic in the fed state. Nonetheless, we have established the framework for a long-term, glucose-responsive treatment for T1DM from which further improvements can be made. Keywords Open AccessAn Open...

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Glucose-regulated insulin production in the liver improves glycemic control in type 1 diabetic mice

Cited by 7 publications

References 54 publications

mRNA destabilization improves glycemic responsiveness of transcriptionally regulated hepatic insulin gene therapy in vitro and in vivo

mRNA destabilization improves glycemic responsiveness of transcriptionally regulated hepatic insulin gene therapy in vitro and in vivo

Long-Term Efficacy and Safety of Insulin and Glucokinase Gene Therapy for Diabetes: 8-Year Follow-Up in Dogs

Long-term correction of diabetic hyperglycemia through glucose-responsive hepatic insulin production using lentivirus

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