Advances and potential of gene therapy for type 2 diabetes mellitus

Figures & data

Table 1. Potential targets can be used for T2DM gene therapy.

Class	Gene(s)	Main function	Reference
Genes regulating glucose homeostasis	GLUTs	Re-absorption of filtered glucose from the kidney into the bloodstream	[23]
	SGLTs	Play a fundamental role in the muscle and liver glucose fluxes	[24]
	FGFs	Play significant roles in glucose homeostasis	[25]
	SIRT6	Associated with increased glycolysis and GLUTs expression	[33]
Genes improving insulin secretion and/or sensitivity	GLP-1 and its analogs/agnoists	Increase beta-cell survival, stimulate insulin gene expression, and secretion	[35]
	GPGRs and their agonists	Stimulate insulin and GLP-1 secretion	[36]
	CTB-APSL	Promotes insulin secretion and insulin resistance	[40]
	IKK ɛ, TBK1	Associated with weight reduction, insulin resistance, fatty liver, and inflammation	[38]
Genes ameliorating diabetic induced complications	IL-1β	Associated with inflammation and β-cell failure	[39]
	ADPN	Ameliorates diabetic nephropathy	[45]
	TGF-α	Plays a role in DKD associated with nephron reduction	[41]
	NLRP3	Ameliorates diabetic cardiomypathy	[47]
	CDKN2A/2B	Associated with T-cell phenotype modulation and chronic inflammation	[43]
	HSP70	Associated with mitochondrial bioenergetics and diabetic sensory neuropathy	[44]
	MicroRNAs	Involved in regulating the diabetic microvasculature	[46]

Note: SGLTs, sodium-glucose co-transporters; GLUTs, glucose transporters; FGFs, fibroblast growth factors; SIRT6, Sirtuin 6; GLP-1, glycogen like peptide 1; GPGRs, G protein–coupled receptors; CTB-APSL, cholera toxin B subunit and active peptide from shark liver; ADPN, adiponectin; TGF-α, transforming growth factor-alpha; NLRP3, nucleotide-binding oligomerization domain-like receptor protein 3; DKD, diabetic kidney disease; HSP70, heat shock protein 70.

Table 2. Gene therapy of T2DM in the last five years.

Gene target	Delivery route/method	Treatment period	Main results	Reference
GLP-1	OA/recombinant Lactococcus lactis	11 hours	Significant decrease (p < 0.05) in blood glucose levels during 2–11 hours post dosing and a significant increase in insulin levels	[60]
5 × GLP-1	OA/recombinant Lactobacillus paracasei	16 days	Has no effect on glucose levels	[61]
10 × GLP-1	OA/recombinant Saccharomyces cerevisiae	16 days	Ameliorates weight loss, decreases blood glucose levels	[62]
GLP-1	OA/plasmid DNA encoding GLP-1	32 days	Decreases diabetic glucose levels to the normoglycemic range with significant weight reduction	[65]
GLP-1	IP/HIV based lentiviral vector encoding GLP-1	24 weeks	Reduces blood glucose levels, improves insulin sensitivity and glucose tolerance, normalize glycaemia, and plasma triglyceride	[63]
Exendin-4	Submandibular gland injection/dsAAV packaged Exendin-4	8 weeks	Increases insulin levels, decreases blood glucose levels	[64]
NLRP3	Jugular-vein injection/NLRP3-miRNA	8 weeks	Gene silencing of NLRP3 ameliorates diabetic cardiomyopathy	[42]
ADPN	IP/recombinant plasmid mediated by lipofectamine	12 weeks	Ameliorates diabetic nephropathy, attenuates urine albumin excretion, reduces the generation of ROS, and prevents interstitial fibrosis	[45]
mGCK	SC/adenovirus-based vector encoding mGCK	8 weeks	Decreases blood glucose levels over a period of 12 and 70 days without inducing hypoglycemia	[66]
VIP	IP/HIV based lentiviral vector encoding VIP	4 weeks	Improves insulin sensitivity, glucose tolerance and reduces serum triglyceride/cholesterol levels	[67]
ANGPTL8	UTMD delivery of human ANGPTL8 gene plasmids	4 weeks	Promotes the proliferation of beta cells, improves glucose tolerance, and the fasting blood insulin level	[68]
FGF21	IV/liver specific AAV encoding a murine optimized FGF21	69 weeks	Reduces body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance	[69]

Note: ADPN, adiponectin; oral administration, OA; IP, intraperitoneal injection; SC, subcutaneous injection; IV, intravenous injection; dsAAV, double-stranded adeno-associated virus; FGF21, fibroblast growth factor 21; GLP-1, glucagon like peptide 1; mGCK, mutant glucokinase; NLRP3, nucleotide-binding oligomerization domain-like receptor protein 3; UTMD, ultrasound-targeted microbubble destruction; VIP, vasoactive intestinal peptide.

Yonamine CY, Pinheiro-Machado E, Michalani ML, et al. Resveratrol improves glycemic control in type 2 diabetic obese mice by regulating glucose transporter expression in skeletal muscle and liver. Molecules. 201722:1180.

 Web of Science ®Google Scholar

Norton L, Shannon CE, Fourcaudot M, et al. Sodium-glucose co-transporter (SGLT) and glucose transporter (GLUT) expression in the kidney of type 2 diabetic subjects. Diabetes Obes Metab. 2017;19:1322–1326.

 PubMed Web of Science ®Google Scholar

Imamura T. Physiological functions and underlying mechanisms of fibroblast growth factor (FGF) family members: recent findings and implications for their pharmacological application. Biol Pharm Bull. 2014;37:1081–1089.

 PubMed Web of Science ®Google Scholar

Sociali G, Magnone M, Ravera S, et al. Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model. FASEB J. 2017;31:3138–3149.

 PubMed Web of Science ®Google Scholar

Tasyurek MH, Altunbas HA, Canatan H, et al. GLP-1-mediated gene therapy approaches for diabetes treatment. Expert Rev Mol Med. 2014;16:e7–20.

 PubMed Web of Science ®Google Scholar

Reimann F, Gribble FM. G protein-coupled receptors as new therapeutic targets for type 2 diabetes. Diabetologia. 2016;59:229–233.

 PubMed Web of Science ®Google Scholar

Liu Y, Gao Z, Guo Q, et al. Anti-diabetic effects of CTB-APSL fusion protein in type 2 diabetic mice. Mar Drugs. 2014;12:1512–1529.

 PubMed Web of Science ®Google Scholar

Oral EA, Reilly SM, Gomez AV, et al. Inhibition of IKKɛ and TBK1 improves glucose control in a subset of patients with type 2 diabetes. Cell Metab. 2017;26:157–170.

 PubMed Web of Science ®Google Scholar

Zhang Y, Yu XL, Zha J, et al. Therapeutic vaccine against IL-1β improved glucose control in a mouse model of type 2 diabetes. Life Sci. 2018;192:68–74.

 PubMed Web of Science ®Google Scholar

Yuan F, Liu YH, Liu FY, et al. Intraperitoneal administration of the globular adiponectin gene ameliorates diabetic nephropathy in Wistar rats. Mol Med Rep. 2014;9:2293–2300.

 PubMed Web of Science ®Google Scholar

Heuer JG, Harlan SM, Yang DD, et al. Role of TGF-alpha in the progression of diabetic kidney disease. Am J Physiol Renal Physiol. 2017;312:F951–F962.

 PubMed Web of Science ®Google Scholar

Kuşcu L, Sezer AD. Future prospects for gene delivery systems. Expert Opin Drug Deliv. 2017;14:1205–1215.

 PubMed Web of Science ®Google Scholar

VinuÉ Á, MartÍnez-HervÁs S, Herrero-Cervera A, et al. Changes in CDKN2A/2B expression associate with T-cell phenotype modulation in atherosclerosis and type 2 diabetes mellitus. Transl Res. 2019;203:31–48.

 PubMed Web of Science ®Google Scholar

Ma J, Farmer KL, Pan P, et al. Heat shock protein 70 is necessary to improve mitochondrial bioenergetics and reverse diabetic sensory neuropathy following KU-32 therapy. J Pharmacol Exp Ther. 2014;348:281–292.

 PubMed Web of Science ®Google Scholar

Zhang Y, Sun X, Icli B, et al. Emerging roles for microRNAs in diabetic microvascular disease: novel targets for therapy. Endocr Rev. 2017;38:145–168.

 PubMed Web of Science ®Google Scholar

Agarwal P, Khatri P, Billack B, et al. Oral delivery of glucagon like peptide-1 by a recombinant Lactococcus lactis. Pharm Res. 2014;31:3404–3414.

 PubMed Web of Science ®Google Scholar

Lin Y, Krogh-Andersen K, Pelletier J, et al. Oral delivery of pentameric glucagon-like peptide-1by recombinant Lactobacillus in diabetic rats. PLoS One. 2016;11:e0162733.

 PubMed Web of Science ®Google Scholar

Wu R, Chao M, Li X, et al. Construction of yeast strains expressing long-acting glucagon-like peptide-1(GLP-1) and their therapeutic effects on type 2 diabetes mellitus mouse model. Hereditas. 2015;37:183–191.

 PubMedGoogle Scholar

Nurunnabi M, Lee SA, Revuri V, et al. Oral delivery of a therapeutic gene encoding glucagon-like peptide 1 to treat high fat diet-induced diabetes. J Control Release. 2017;268:305–313.

 PubMed Web of Science ®Google Scholar

Tasyurek HM, Altunbas HA, Balci MK, et al. Therapeutic potential of lentivirus-mediated glucagon-like peptide-1 gene therapy for diabetes. Hum Gene Ther. 2018;29:802–815.

 PubMed Web of Science ®Google Scholar

Wang J, Wen J, Bai D, et al. Injection of submandibular gland with recombinant exendin-4 and adeno-associated virus for the treatment of diabetic rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2015;40:1179–1185.

 PubMedGoogle Scholar

Luo B, Li B, Wang W, et al. NLRP3 gene silencing ameliorates diabetic cardiomyopathy in a type 2 diabetes rat model. PLoS One. 2014;9:e104771.

 PubMed Web of Science ®Google Scholar

Lu G, Teng X, Zheng Z, et al. Overexpression of a glucokinase point mutant in the treatment of diabetes mellitus. Gene Ther. 2016;23:323–329.

 PubMed Web of Science ®Google Scholar

Tasyurek HM, Eksi YE, Sanlioglu AD, et al. HIV-based lentivirus-mediated vasoactive intestinal peptide gene delivery protects against DIO animal model of type 2 diabetes. Gene Ther. 2018;25:269–283.

 PubMed Web of Science ®Google Scholar

Chen J, Chen S, Huang P, et al. In vivo targeted delivery of ANGPTL8 gene for beta cell regeneration in rats. Diabetologia. 2015;58:1036–1044.

 PubMed Web of Science ®Google Scholar

Jimenez V, Jambrina C, Casana E, et al. FGF21 gene therapy as treatment for obesity and insulin resistance. EMBO Mol Med. 2018;10:e8791.

 PubMed Web of Science ®Google Scholar