DRUG TARGETS
Over 30 validated targets for either type 2 diabetes and/or obesity are listed below. For a longer description, a list of compounds in development, discontinued or on the market for each target, illustrations and references, please click on the target name.
| Target name | Indication | Short description |
| 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) | Type 2 diabetes | 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is a bidirectional enzyme that preferentially catalyzes the conversion of the inactive glucocorticoid (cortisone) to its active (cortisol) form. Since cortisol increases gluconeogensis, inhibition of 11beta-HSD1 would be expected to improve insulin resistance. |
| Acetyl-CoA carboxylase 2 (ACC2) | Type 2 diabetes | ACC2 is an enzyme that catalyzes the conversion of acetyl-CoA to malonyl-CoA, a key intermediate in the biosynthesis of fatty acid and a regulator of fatty acid oxidation. Inhibition of ACC2 should reduce fatty acid biosynthesis and increase fatty acid oxidation. |
| Alpha-glucosidase | Type 2 diabetes | Alpha-glucosidase is an enzyme that catalyzes the degradation of glycogen polymers to absorbable monosaccharides (such as glucose) in the intestine. Alpha-glucosidase inhibitors reversably decrease the absorption of carbohydrates by temporarily binding to the enzyme. |
| Amylin | Obesity and type 2 diabetes | Amylin is a hormone that is co-secreted with insulin by pancreatic beta-cells in response to different stimuli such as nutrient ingestion, incretin hormones and neural input, and whose actions results in inhibition of glucagon secretion, reduction of meal size and inhibition of gastric emptying. |
| Dipeptidyl peptidase IV (DPPIV / DPP-4) | Type 2 diabetes | DPP-4 is a membrane associated serine protease that inactivates peptides, neuropeptides, hormones, cytokines and chemokines. In glucose metabolism, DPP-4 inactivates incretin hormones (GLP-1 and GIP) in the gastrointestinal tract that lower blood glucose. The inhibition of DPP-4 decreases incretin inactivation thereby increasing glucose-dependent insulin secretion. |
| Endocannabinoids (CB1) | Obesity and type 2 diabetes | Endocannabinoids (ECs) promote energy conservation by decreasing energy expenditure and increasing food intake when binding to cannabinoid receptor type 1 (CB1) located in the brain and in peripheral tissues. CB1 inhibitors are intended to suppress appetite. |
| FBPase (Fructose 1,6-diphosphatase / fructose 1,6 biphophatase) | Type 2 diabetes | FBPase is an enzyme that catalyzes the irreversible hydrolysis of fructose-1,6 biphosphate to fructose-6-phosphate, an important step in the gluconeogenesis pathway. This permits endogenous glucose production from gluconeogenic amino acids, glycerol or lactate. |
| Gastrin | Type 2 diabetes | Gastrin is a peptide hormone that regulates gastric acid secretion, essential for initiation of food digestion. Gastrin has also been shown to stimulate growth of pancreatic beta-cells, induce islet regeneration and inhibit autoimmune beta-cell destruction. |
| Ghrelin | Obesity | Ghrelin, mainly produced in the stomach, acts on the hypothalamus to stimulate apetite and food intake and decrease energy expenditure by limiting fat catabolism and lipolysis(orexigenic activity). Ghrelin has the opposite effect of leptin. |
| Glucagon receptor (GCGR) | Type 2 diabetes | When blood glucose levels drop, pancreatic alpha-cells secrete glucagon which signals, through the glucagon receptors, the conversion of fatty acids from adipose tissue into glucose by the liver, leading to the release of glucose into the blood (an effect opposite to that of insulin). |
| Glucagon-like peptide-1 (GLP-1) | Obesity and type 2 diabetes | GLP-1 is an incretin hormone secreted by the intestine following nutrient absorption or either neural or endocrine signals. GLP-1 will increase insulin secretion and satiety and inhibit glucagon secretion and gastric emptying. |
| Glucocorticoid receptor (GR) | Type 2 diabetes | The glucocorticoid receptor belongs to the steroid nuclear receptor superfamily and modulates gene transcription, particularly transcription of genes involved in metabolic regulation such as blood glucose levels, gluconeogenesis and mobilization of amino and fatty acids. |
| Glucokinase (GK) | Type 2 diabetes | The glucokinase is the rate limiting enzyme that, in response to high blood sugar levels, catalyses the phosphorylation of glucose into glucose 6-phosphate, a reaction step in the glycogen synthesis pathway that occurs in the liver. |
| Glucose-dependent insulinotropic polypeptide (GIP) | Type 2 diabetes | Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone secreted by the intestine in response to food ingestion, induces insulin secretion. GIP also promotes energy storage by increasing lipogenesis in adipose tissue. |
| Glycogen phosphorylase | Type 2 diabetes | Glycogen phosphorylase is an enzyme directly involved in the breakdown of glycogen into glucose in response to low blood glucose levels. |
| Histamine H1 and H3 receptors | Obesity | Histamine is a neurotransmitter having an anorectic effect. Regulation of body weight by histamine involves central H1 and H3 receptors. Histamine acts on H1 receptors to suppress food intake and on H3-autoreceptors to inhibit further histamine release. |
| K ATP channels (metiglinides and sulfonylureas) | Obesity | KATP channels in pancreatic beta-cells, also named sulfonylurea receptor (SUR), are regulated by the ATP/ADP ratio. Closure of these channels results in membrane depolarization which stimulates insulin secretion. Drugs from the metiglinides and sulfonylureas classes target the KATP channel. |
| Leptin | Obesity | Leptin is mainly released by adipocytes and sends a signal to the central nervous system to suppress food intake and increase energy expenditure (anorexigenic activity). Leptin has the opposite effect of ghrelin. |
| Lipase | Obesity | Gastric and pancreatic lipases are key enzymes that convert triglyceride (triacylglycerols) to free fatty acids and monoacylglycerols in the intestinal tract thereby allowing the absorption of dietary fat. |
| Melanin-concentrating hormone (MCH) receptor | Obesity | Melanin-concentrating hormone (MCH) is a potent orexigenic neuropeptide, present in the lateral hypotahlamus and zona incerta in the brain, that responds to metabolic signals to modulate feeding behaviours and energy balance via MCH receptor activation. |
| Melanocortin receptors (MCR) | Obesity | Of the five melanocortin receptors, only MC3R and MC4R, present in the hypothalamus, are involved in the contorl of food intake and expenditure. Activation of these receptors by melanocortin peptides reduces meal size and induces meal termination while their de-activation by agouti-related protein (AgRP) stimulates feeding behaviour. |
| Metformin | Type 2 diabetes | Metformin is an insulin sensitizer that acts preferentially to inhibit glucose production. Metformin acts on multiple targets and its complete mechanism of action has not yet been fully elucidated. Metformin is the only drug in the biguanide class. |
| Monoaminergic neurotransmitter | Obesity | The monoamine system includes the neurotransmitters serotonin (5-HT), dopamine and noradrenaline involved in hunger control, satiation and satiety. |
| Neuropeptide Y (NPY) receptors | Obesity | The NPY receptor family is involved in modulation of food intake and is comprised of five subtypes (Y1 to Y5). Activation of Y1 and Y5 receptors mediates the hunger signalling action, while Y2 and Y4 receptor-activation is primarily involved in satiety signals. These receptors differ in their function and affinity for PYY (peptide Y), NPY (neuropeptide Y) and PP (pancreatic peptide). |
| Peroxisome proliferator-activated receptors (PPAR) apha, beta, gamma | Type 2 diabetes | Peroxisome proliferator activated receptors (PPARs) are lipid-activated transcription factors that belong to the steroid/thyroid/retinoic acid nuclear receptor superfamily and target a group of genes participating in the lipid homeostasis. |
| Protein tyrosine phosphatase-1B (PTP1B) | Type 2 diabetes | PTP1B is an enzyme that removes phosphate from tyrosine residues and acts as a negative regulator of insulin and leptin signalling pathways. |
| s123456 | Obesity | |
| Sodium-Glucose Linked Transporter (SGLT) | Type 2 diabetes | SGLT are proteins that control cellular glucose uptake in the intestine and kidneys by using energy generated by the electrochemical gradient of sodium ions. |
| Stearoyl-CoA desaturase (SCD) | Obesity and type 2 diabetes | Stearoyl-CoA desaturase is a regulatory enzyme that converts saturated fatty acid into monounsaturated fatty acids by acting through the lipogenensis pathway. |