Hepatic Insulin Gene Therapy in Insulin-Dependent Diabetes Mellitus

Nett, Philipp C.; Sollinger, Hans W.; Alam, Tausif

doi:10.1046/j.1600-6143.2003.00221.x

Cited by 25 publications

(12 citation statements)

References 111 publications

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“…It is difficult to reproduce such efficient regulation by engineering extrapancreatic tissue. Although many advances in hepatic insulin gene therapy have been made over the past few years, precise regulation of insulin production and secretion is still a major challenge (7,28,29). In our approach, insulin was constitutively expressed at basal levels in skeletal muscle of diabetic mice, which allowed the maintenance of normoglycemia between meals.…”

Section: Discussionmentioning

confidence: 99%

Reversal of Type 1 Diabetes by Engineering a Glucose Sensor in Skeletal Muscle

Mas

Montané²,

Anguela³

et al. 2006

Diabetes

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Type 1 diabetic patients develop severe secondary complications because insulin treatment does not guarantee normoglycemia. Thus, efficient regulation of glucose homeostasis is a major challenge in diabetes therapy. Skeletal muscle is the most important tissue for glucose disposal after a meal. However, the lack of insulin during diabetes impairs glucose uptake. To increase glucose removal from blood, skeletal muscle of transgenic mice was engineered both to produce basal levels of insulin and to express the liver enzyme glucokinase. After streptozotozin (STZ) administration of double-transgenic mice, a synergic action in skeletal muscle between the insulin produced and the increased glucose phosphorylation by glucokinase was established, preventing hyperglycemia and metabolic alterations. These findings suggested that insulin and glucokinase might be expressed in skeletal muscle, using adeno-associated viral 1 (AAV1) vectors as a new gene therapy approach for diabetes. AAV1-Ins؉GK-treated diabetic mice restored and maintained normoglycemia in fed and fasted conditions for >4 months after STZ administration. Furthermore, these mice showed normalization of metabolic parameters, glucose tolerance, and food and fluid intake. Therefore, the joint action of basal insulin production and glucokinase activity may generate a "glucose sensor" in skeletal muscle that allows proper regulation of glycemia in diabetic animals and thus prevents secondary complications. Diabetes 55: 1546 -1553, 2006

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Section: Discussionmentioning

confidence: 99%

Reversal of Type 1 Diabetes by Engineering a Glucose Sensor in Skeletal Muscle

Mas

Montané²,

Anguela³

et al. 2006

Diabetes

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“…Particularly for type 1 diabetes, gene therapy provides various ways to deliver exogenous insulin to the liver (see ref. [85]). Many viral vectors based on lentivirus, retrovirus, or adeno-associated virus can provide long-term transgene expression.…”

Section: Strategies and Approachesmentioning

confidence: 99%

Reduction of Hepatic Glucose Production as a Therapeutic Target in the Treatment of Diabetes

Wu¹,

Okar²,

Kang³

et al. 2005

curr drug targets immune endocr metabol disord

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There has been an alarming increase in the population diagnosed with diabetes worldwide. Although there is an ongoing debate as to the role of liver in the pathogenesis of diabetes, reduction of hepatic glucose production has been targeted as a strategy for diabetes treatment. Indeed, reduction of hepatic glucose production can be achieved through modulation of both hepatic and extra-hepatic targets. This review describes the role of the liver in the control of glucose homeostasis. Gluconeogenesis and glycogenolysis are pathways for glucose production, whereas glycolysis and glycogenesis are pathways for glucose utilization/storage. At the biochemical and molecular level, the metabolic and regulatory enzymes integrate hormonal and nutritional signals and regulate glucose flux in the liver. Modulating either activities of or gene expression of these metabolic enzymes can control hepatic glucose production. Dysfunction of one or several enzyme(s) due to insulin deficiency or resistance results in increases in fluxes of glycogenolysis and gluconeogenesis and/or decreases in fluxes of glycolysis and glycogenesis, which thereby lead to glucose generation exceeding glucose consumption/disposal, as well as dysregulation of lipid metabolism. Activation of enzymes that promote glucose utilization/storage and/or inhibition of enzymes that reduce glucose generation achieve reduction of hepatic glucose production, and hence lower levels of plasma glucose in diabetes. This is also beneficial for the correction of dyslipidemia. Therefore, many enzymes are viable therapeutic targets for diabetes.

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“…T1D is a chronic autoimmune disease that is related to multiple organ inflammation, including the pancreas, kidney, liver and spleen (Alanentalo et al, 2010;Corte-Real, Duarte, Tavares, & Penha-Goncalves, 2009;Tsui, Razavi, Chan, Yantha, & Dosch, 2007). Among the visceral organs, the liver is a major target organ of insulin action that plays a pivotal role in glucose homeostasis (Nett, Sollinger, & Alam, 2003). Therefore, a change in the liver is an important target for diabetic pathogenesis evaluation.…”

Section: Introductionmentioning

confidence: 99%