Modulation of glucose-6-phosphatase translocase expression

Abstract

Compositions and methods are provided for decreasing blood glucose levels in an animal, comprising administering to said animal an antisense inhibitor of glucose-6-phosphatase translocase expression alone or in combination with at least one glucose-lowering drug. Also provided are compositions and methods for treating diabetes and other metabolic disorders.

1 . A single-stranded oligonucleotide 13 to 30 nucleotides in length which is targeted to and hybridizable with a nucleic acid molecule encoding glucose-6-phosphatase translocase comprising at least two chemical modifications selected from a modified internucleoside linkage, a modified nucleobase, or a modified sugar, wherein said oligomeric compound inhibits glucose-6-phosphatase translocase expression. 
     
     
         2 . The single-stranded oligonucleotide of  claim 1  wherein said oligomeric compound is a chimeric oligonucleotide having a first region comprising deoxynucleotides and a second and third region comprising 2′-O-(2-methoxyethyl)nucleotides. 
     
     
         3 . The single-stranded oligonucleotide of  claim 1  wherein said oligomeric compound is a chimeric oligonucleotide comprising a ten deoxynucleotide region flanked on both the 5′ and 3′ ends with five 2′-O-(2-methoxyethyl)nucleotides and wherein each internucleoside linkage is a phosphorothioate. 
     
     
         4 . The single-stranded oligonucleotide of  claim 1  wherein said oligomeric compound inhibits expression of glucose-6-phosphatase translocase by at least 35%. 
     
     
         5 . An oligomeric compound  13  to  30  nucleotides in length which is targeted to and hybridizable with a nucleic acid molecule encoding glucose-6-phosphatase translocase comprising at least two chemical modifications selected from a modified internucleoside linkage, a modified nucleobase, or a modified sugar, wherein said oligomeric compound inhibits expression of glucose-6-phosphatase translocase by at least 35% and is selected from SEQ ID NOs 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 40, 41, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 52, 53, 54, 55, 56, 57, 57, 58, 59, 60, 61, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 157, 158, 159, 160, 161, 163, 164, 165, 166, 167, 168, 169, 171, 172, 173, 175, 176, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 190, 192, 193, 194, 195, 196, 198, 199, 200, or 201. 
     
     
         6 . A method of lowering glucose in an animal, comprising the step of administering a compound of  claim 1  to said animal. 
     
     
         7 . The method of  claim 6 , wherein the glucose is blood glucose. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 6 , wherein said animal has condition selected from diabetes, type II diabetes, insulin resistance, insulin deficiency, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperfattyacidemia, liver steatosis, metabolic syndrome, cardiovascular disease, or a cardiovascular risk factor. 
     
     
         10 . The method of  claim 6 , wherein said animal has a condition associated with metabolic syndrome. 
     
     
         11 . A method of lowering triglycerides in an animal, comprising the step of administering a compound of  claim 1  to said animal. 
     
     
         12 . (canceled) 
     
     
         13 . A method of lowering cholesterol in an animal, comprising the step of administering a compound of  claim 1  to said animal. 
     
     
         14 . The method of  claim 6 , further comprising the step of administering at least one additional glucose-lowering drug wherein the glucose-lowering drug is a hormone, a hormone mimetic, a sulfonylurea, a biguanide, a meglitinide, a thiazolidinedione, or an alpha glucosidase inhibitor. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 14  wherein the hormone or hormone mimetic is insulin, GLP-1 or a GLP-1 analog. 
     
     
         17 . The method of  claim 16  wherein the GLP-1 analog is exendin-4 or liraglutide. 
     
     
         18 . The method of  claim 14  wherein the sulfonylurea is acetohexamide, chlorpropamide, tolbutamide, tolazamide, glimepiride, a glipizide, glyburide or a gliclazide. 
     
     
         19 . The method of  claim 14  wherein the biguanide is metformin. 
     
     
         20 . The method of  claim 14  wherein the meglitinide is nateglinide or repaglinide. 
     
     
         21 . The method of  claim 14  wherein the thiazolidinedione is pioglitazone, rosiglitazone or troglitazone. 
     
     
         22 . The method of  claim 14  wherein the alpha-glucosidase inhibitor is acarbose or miglitol. 
     
     
         23 . The method of  claim 14 , wherein said animal has or is suspected of having a condition selected from diabetes, type II diabetes, insulin resistance, insulin deficiency, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hyperfattyacidemia, liver steatosis, metabolic syndrome, cardiovascular disease, or a cardiovascular risk factor.