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Analysis of Secondary Phenotype Data under Case-Control Designs
Published in Ørnulf Borgan, Norman E. Breslow, Nilanjan Chatterjee, Mitchell H. Gail, Alastair Scott, Christopher J. Wild, Handbook of Statistical Methods for Case-Control Studies, 2018
Guoqing Diao, Donglin Zeng, Dan-Yu Lin
Although the primary objective of case-control studies is to assess the effects of genetic variants between cases and controls, secondary phenotypes are often collected in such studies without much extra cost. For example, in the Diabetes Genetics Initiative (DGI) study, there were 1,464 patients with type 2 diabetes and 1,467 controls from Finland and Sweden, while at the same time, a variety of secondary phenotype traits were available for these patients, including anthropometric measures, glucose tolerance and insulin secretion, lips and apoliporoteins and blood pressure. These secondary phenotypes are typically the exposures/risk-factors of interest for the main outcome. In the Wellcome Trust Case Control Consortium (WTCCC), a case-control study consisting of 1,924 U.K. type-2 diabetes patients and 2,938 U.K. population controls, body mass index (BMI) and adult height were also measured as secondary traits in the study. With the availability of second phenotype information, it is cost-effective to study the association between genetic variants and these additional traits without need to conduct new studies. Indeed, the DGI study identified association of a particular single nucleotide polymorphism (SNP) in an intron of glucokinase regulatory protein with serum triglycerides in both case and control groups.
Anti-Diabetic Drugs
Published in Awanish Kumar, Ashwini Kumar, Diabetes, 2020
Glucokinase (GK), also known as hexokinase IV, is a glucose-phosphorylating enzyme expressed exclusively in the liver and β-cells that plays a crucial role in glucose homeostasis. It acts as a glucose-sensing enzyme in β-cells and plays a critical role in phosphorylating glucose to glucose-6-phosphate during glycolysis and glycogen synthesis in the liver. Apart from β-cells, they also play a role in glucose sensing in intestinal cells (enterocytes) and certain specialised neurons in the hypothalamus. Its effect is primarily induced in hepatocytes by insulin, while glucose acts as basic inducer of GK in β-cells. GK has a low affinity of glucose in the physiological range of 5 mmol/L to 7 mmol/L (90 mg/dL to 126 mg/dL) and it also lacks a feedback inhibition from its primary product glycose-6-phosphate (G6P). When the plasma glucose rises post-prandial, the β-cells sense this change and the uninterrupted influx of glucose into β-cells through GLUT2 leads to glucose fluctuation sensing and glucose-stimulated insulin secretion (GSIS). As the GK of β-cells, unlike other hexokinases, is not inhibited by G6P, its activity is essential in continuous sensing of glucose to stimulate GSIS. GK is said to exist in two different conformations, namely ‘super open’ and ‘closed’. The super open conformation is the inactive form, while the closed conformation is the active state of GK. The conformation changes from super open to closed after glucose binding. Between super open and closed conformation, there is an intermediate ‘open’ confirmation. When the glucose binds to the super open form, the GK takes the closed structure. Upon binding of ATP, GK converts glucose to G6P. As soon as the G6P is released, the GK comes to the intermediate open form and binds another glucose molecule, if present. If glucose is not present, it gets back to the super open conformation. Thus, a continuous flux of glucose leads to a change of GK between closed and open, rather than closed and super open. In the liver, the action of GK is controlled by a protein known as glucokinase regulatory protein (GKRP). In low glucose condition (or high fructose-6-phosphate level), GKRP remains bound to GK, and sequesters it into the nucleus, rendering it inactive. As soon as the glucose level rises in the body (or there is an increase in fructose-1-phosphate), GKRP gets released and GK moves back to the cytoplasm and gets bound to glucose. This is essential to glycogenesis and glycolysis. In the low glucose state, the ‘sensing’ of GKRP in the liver prevents more glucose from getting converted to glycogen. As soon as the blood glucose rises, the glycogenesis starts again [45–47].
Type 1 diabetes: key drug targets and how they could influence future therapeutics
Published in Expert Opinion on Therapeutic Targets, 2023
Yoon Kook Kim, Kashif M. Munir, Stephen N. Davis
Glucokinase serves as a glucose sensor in pancreatic islet cells promoting glucose-stimulated insulin secretion. Activation of glucokinase in the liver promotes hepatic glucose uptake and glycogen synthesis and storage[67], and mutations in glucokinase have shown to lead to dysglycemia [68]. TTP399 is an oral, small molecule, liver selective glucokinase activator. A two-part study, randomly assigning 20 patients with T1DM in Part 1 and 85 patients in Part 2 to TTP399 800 mg vs placebo, demonstrated reduction of HbA1c over 12 weeks of −0.7% in Part 1 and −0.21% in Part 2 [69]. Despite improvements in HbA1c, TTP399 treated patients also showed a 40% reduction in hypoglycemia without increase in episodes of diabetic ketoacidosis. This is because in the liver, glucokinase is notably regulated by its interaction with the glucokinase regulatory protein, which ensures its activation only in the setting of hyperglycemia. Dorzagliatin is a dual-acting (pancreatic and hepatic) glucokinase activator in late phase trials for the treatment of type 2 diabetes [70,71]. Preliminary data show this class as a potential therapy for individuals with type 1 and type 2 diabetes. TTP399 was recently granted breakthrough therapy designation by the Food and Drug Administration (FDA) in the United States as an adjunctive therapy for patients with T1DM. With further studies, glucokinase activation may play a larger role in safe pharmacologic treatment of T1DM.
Sirtuins as therapeutic targets for improving delayed wound healing in diabetes
Published in Journal of Drug Targeting, 2022
Fathima Beegum, Anuranjana P. V., Krupa Thankam George, Divya K. P., Farmiza Begum, Nandakumar Krishnadas, Rekha R. Shenoy
SIRT 2 has a vital role in maintaining hepatic glucose uptake (HGU) and adipocytes tissue development [87]. SIRT 2 controls glucose homeostasis by facilitating HGU and promoting phosphoenolpyruvate carboxykinase (PEPCK1) degradation [88]. HGU is regulated by glucokinase and glucose-6-phosphatase. Role of SIRT 2 on HGU mediated by glucokinase regulatory protein (GKRP) has been studied. SIRT 2 affects HGU as GKRP acetylation has inverse relationship with SIRT 2 expression. Besides HGU-dependent glucose homeostasis, SIRT 2 prevents ubiquitylation dependent PGPCK1 degradation, thereby modulates glucose homeostasis. The decreased SIRT 2 expression results in mitochondrial dysfunction, extracellular signal-regulated kinase (ERK) activation and enhanced production of ROS [88].
Advances in computer-aided drug design for type 2 diabetes
Published in Expert Opinion on Drug Discovery, 2022
Wanqiu Huang, Luyong Zhang, Zheng Li
Jr et al. identified a series of GK glucokinase regulatory protein (GK-GKRP) disruptors based on SBDD. Firstly, the lead compound was screened [90] using the HTS method, and the ability of compound 27 to disrupt GK-GKRP pathway was validated by in vitro experiments. As shown in Figure 5, the structure of compound 27 was divided into A, B, and C rings. A ring entered the left pocket comprising residues Arg215 and Ala214. The aryl ring was pointed into a hydrophobic cavity by generating van der Waals forces with Ala521, Val28, and Glu32, whereas the tertiary hydroxyl group formed hydrogen bond with Arg525. To improve the pharmacokinetics of compound 27, further structural optimization was performed based on the co-crystal structure of compound 27 bound to hGKRP. Compound 28 found to have superior cellular and hypoglycemic activities in animals. Then, the X-ray co-crystal of compound 28 with hGKRP showed that the substituent group of the B ring occupied a new cavity and produced new hydrogen bond with Ile11. However, compound 28 still had poor activity, low exposure, and was susceptible to metabolism [88]. Therefore, metabolite identification and SBDD approaches were adopted for the structural optimization of compound 28. The highly potent and metabolically stable GK-GKRP disruptor compound 29 was obtained by replacing thiophene with a methyl morpholine group of compound 28. Compound 29 formed new hydrogen bonds with Gly181 and Met213. After analyzing the key receptor–ligand interactions of compound 30 showed an unoccupied new cavity in the protein. Therefore, optimal compound 31 was obtained by modifying the 5-position of N-pyridine of compound 30. Indeed, the X-ray crystal structure of compound 31 suggested that the 3-pyridine ring occupied a novel pocket, and the new binding mode produced favorable contacts with the top face and edge-to-face of the binding pocket (Figure 5). Moreover, the authors [91] described a new GK-GKRP complex disruptor with an aryl sulfone scaffold. The X-ray crystal structure, conformational analysis, and SAR information of compound 32 were used for drug design. All these efforts led to the discovery of compound 33, and its diol portion formed interaction with Arg525. Furthermore, compound 33 showed low clearance rate, high oral bioavailability, and pharmacological activity. In conclusion, the authors identified a series of highly potent GK-GKRP disruptors based on the CADD method, which is inspiring for development of new drugs in the future.