Release of transgenic human insulin from gastric g cells: a novel approach for the amelioration of diabetes.
We explored the hypothesis that meal-regulated release of insulin from gastric G cells can be used for gene therapy for diabetes. We generated transgenic mice in which the coding sequence of human insulin has been knocked into the mouse gastrin gene. Insulin was localized specifically to antral G cells of G-InsKi mice by double immunofluorescence staining using antibodies against insulin and gastrin. Insulin extracted from antral stomach of G-InsKi mice decreased blood glucose upon injection into streptozotocin-diabetic mice. Intragastric administration of peptone, a known potent luminal stimulant of gastrin secretion, induced an increase in circulating levels of transgenic human insulin from 10.7 +/- 2 to 23.3 +/- 4 pm in G-InsKi mice. Although G cell-produced insulin decreased blood glucose in G-InsKi mice, it did not cause toxic hypoglycemia. Proton pump inhibitors, pharmacological agents that increase gastrin output, caused a further increase in the circulating levels of gastric insulin (41.5 +/- 2 pm). G cell-produced insulin was released into circulation in response to the same meal-associated stimuli that control release of gastrin. The most striking aspect of the results presented here is that in the presence of the G-InsKi allele, Ins2(Akita/+) mice exhibited a marked prolongation of life span. These results imply that G cell-derived transgenic insulin is beneficial in the amelioration of diabetes. We suggest that an efficient G cells-based insulin gene therapy can relieve diabetic patients from daily insulin injections and protect them from complications of insulin insufficiency while avoiding episodes of toxic hypoglycemia.
Lu
Yu-Chun
YC
Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine at University of California, Los Angeles, California 90095-1786, USA.
Sternini
Catia
C
Rozengurt
Enrique
E
Zhukova
Elena
E
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D003924:Diabetes Mellitus, Type 2 / Q000628:therapy*; D004435:Eating; D005753:Gastric Mucosa / Q000166:cytology / Q000502:physiology; D019863:Gastrin-Secreting Cells / Q000502:physiology*; D005755:Gastrins / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006943:Hyperglycemia / Q000628:therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D001786:Blood Glucose; D005755:Gastrins; D007004:Hypoglycemic Agents; D007328:Insulin