Key Regulator Of Glucose Homeostasis Research Articles

The hypothalamus as a key regulator of glucose homeostasis: emerging roles of the brain renin-angiotensin system.

The regulation of plasma glucose levels is a complex and multifactorial process involving a network of receptors and signaling pathways across numerous organs that act in concert to ensure homeostasis. However, much about the mechanisms and pathways by which the brain regulates glycemic homeostasis remains poorly understood. Understanding the precise mechanisms and circuits employed by the central nervous system to control glucose is critical to resolving the diabetes epidemic. The hypothalamus, a key integrative center within the central nervous system, has recently emerged as a critical site in the regulation of glucose homeostasis. Here, we review the current understanding of the role of the hypothalamus in regulating glucose homeostasis, with an emphasis on the paraventricular nucleus, the arcuate nucleus, the ventromedial hypothalamus, and lateral hypothalamus. In particular, we highlight the emerging role of the brain renin-angiotensin system in the hypothalamus in regulating energy expenditure and metabolic rate, as well as its potential importance in the regulation of glucose homeostasis.

Leptin is a key regulator of glucose homeostasis in obesity

Approximately 9 out of 10 people with type-2 diabetes are overweight. Leptin is a hormone secreted from white fat cells that exerts control over both food intake and energy expenditure. We described the central mechanisms underlying the hypertensive effects of hyperleptinemia in obesity. Work presented here used continuous radiotelemetric glucose monitoring in mice in combination with multiple gold standard techniques in order to determine the effects of dorsomedial hypothalamic (DMH) leptin signalling on peripheral glucose control. A leptin receptor (LepR) antagonist administered directly into the brain impaired DIO mouse glucose tolerance demonstrating that leptin retains the ability to regulate blood glucose concentration in obesity. Knockdown of DMH LepR function using short hairpin adeno-associated virus (AAV) RNA significantly reduced brown adipose tissue (BAT) thermogenesis by -0.8 ± 0.1°C and increased basal blood glucose (14.3 ± 0.6mmol/l to 9.4 ± 0.5mmol/l) and impaired glucose tolerance. Conversely, chemogenic activation of LepR-expressing DMH neurons significantly elevated BAT thermogenesis (1.5 ± 0.2 °C increase). This increased BAT temperature was immediately followed by a decrease in plasma blood glucose concentration (7.6 ± 0.5 mmol/l to 5.8 ± 0.5 mmol/l). Work presented here demonstrates that increasing the activity of LepR expressing neurons in the DMH can improve glucose tolerance in obesity though an elevation of BAT metabolic activity. This work was supported by the National Heart Foundation of Australia (SES), The National Health and Medical Research Council of Australia (SES and MAC). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

1169-P: Circulating MicroRNA-378a-5p and Improvement in Glucose Homeostasis in Response to Weight-Loss Diets: The Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) Trial

Background: MicroRNA-378a (MiR-378a) has been identified as a key regulator of glucose homeostasis and emerging as a promising target for the improvement of glycemic dysregulation including type 2 diabetes. Hypothesis: We assessed associations of circulating miR-378a-5p with improvements in insulin sensitivity and glucose metabolism in a 2-year dietary intervention trial. Methods: Circulating miR-378a-5p levels were measured at baseline and 6 months among 5participants with overweight or obesity. Outcome measurements including fasting glucose, hemoglobin A1c (HbA1c) , fasting insulin, and homeostasis model assessment-of-insulin resistance (HOMA-IR) were assessed at baseline, 6 and 24 months. Results: Higher level of miR-378a-5p was associated with greater fasting glucose (p =0.031) at baseline. Greater decrease in miR-378a-5p was significantly associated with greater improvements in fasting insulin (p =0.012) and HOMA-IR (p =0.017) over 6 months. The initial (6-months) decrease of miR-378a-5p was also significantly related to long-term (24-months) improvements in glucose, insulin, and HOMA-IR (p <0.for all) . Individuals in the lowest tertile group of the baseline miR-378a-5p showed consistently improved fasting insulin and HOMA-IR over 2 years, as compared to those with higher levels of miR-378a-5p (p time*miR-378a-5p =0.015 and 0.007, respectively) . We also found significant interactions between baseline miR-378a-5p and dietary fat in the 6-months change in HbA1c (p = 0.003) ; a lower level of baseline miR-378a-5p showed a greater reduction of HbA1c at 6 months among participants who consumed a low-fat diet. Conclusions: In conclusion, decreased circulating miR-378a-5p levels were related to significant improvements in insulin sensitivity and glucose metabolism in response to dietary weight-loss interventions; and dietary fat intake modified such associations. Disclosure Q.Xue: None. Y.Heianza: None. X.Li: None. H.Deng: None. J.Rood: None. G.Bray: None. F.Sacks: None. L.Qi: None. Funding National Heart, Lung, and Blood Institute (HL071981, HL034594, and HL126024) ;National Institute of Diabetes and Digestive and Kidney Diseases (DK115679, DK091718, and DK100383) ;Fogarty International Center (TW010790)

NLRP3 is a promising target for regulating high glucose-induced inflammatory response in Megalobrama amblycephala

The nucleotide-binding domain, leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) has emerged as a key regulator of glucose homeostasis in mammals, while relevant information are still poorly interpreted in aquatic animals. Herein, we cloned and characterized NLRP3 gene from Megalobrama amblycephala, and analyzed its function in high glucose (HG)-induced inflammation. Full-length cDNA of NLRP3 measured 4380 bp with 3570 bp open reading frame encoding 1189 amino acids, compared with Pimephales promelas, it displayed 90.3% homology. Structural analysis revealed that M. amblycephala NLRP3 processed characteristic domains of pyrin, FISNA, NACHT, CARD and LRRs. Spatial expression analysis displayed NLRP3 was ubiquitously expressed in eight organs/tissues (gill, liver, spleen, intestine, head kidney, white muscle, heart and brain) with largest magnitude in head kidney. After a 13-week nutritional experiment, carbohydrate-enriched (45%) diets significantly upregulated NLRP3 mRNA levels in the liver and white muscle than that of the control (30%) diets. Glucose loading caused a significantly increased NLRP3 mRNA levels in the white muscle and liver, with maximum values got at 1 and 2 h, respectively. Subsequently, the mRNA levels rapidly returned to the basal level at 12 h. As for the in-vitro experiments, both ATP and high-glucose treatments remarkably increased the expression of NLRP3 and pro-inflammatory cytokines (IL1β and IL6) in hepatocytes. Additionally, high-leucine (30 mM) levels remarkably increased NLRP3 protein content and transcriptions of NLRP3, NF-κB, IL1β and IL6 than those of the HG and HG + low leucine (10 mM) treatment groups, while the opposite was true for IL8 and IL10. Overall, our findings indicated that M. amblycephala NLRP3 is highly conserved compared with other vertebrates. NLRP3 participated in the control of HG-induced inflammation, and high-leucine levels could aggravate HG-induced inflammation in hepatocytes of M. amblycephala via NLRP3 activation.

Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1H-pyrazol-1-yl)methyl)phosphonate (BMS-820132).

Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator" 11, which culminated in the discovery of the "partial GK activator" 31 (BMS-820132), are discussed. The synthesis and in vitro and in vivo preclinical pharmacology profiles of 31 and its pharmacokinetics (PK) are described. Based on its promising in vivo efficacy and preclinical ADME and safety profiles, 31 was advanced into human clinical trials.

An Exploratory Study of the Role of Dietary Proteins in the Regulation of Intestinal Glucose Absorption.

Several studies have demonstrated that high protein diets improve glucose homeostasis. Nevertheless, the mechanisms underlying this effect remain elusive. This exploratory study aims to screen and compare the acute effects of dietary proteins from different sources on intestinal glucose absorption. Six dietary proteins from various sources were thus selected and digested thanks to the INFOGEST static gastrointestinal digestion protocol. The digested proteins were able to decrease intestinal glucose absorption in vitro and ex vivo. Moreover, acute ingestion of casein and fish gelatin led to improved glucose tolerance in Wistar rats without significant effect on insulin secretion. In parallel, GLUT2 mRNA expression in enterocytes was decreased following short-term incubation with some of the digested proteins. These results strengthen the evidence that digested protein-derived peptides and amino acids are key regulators of glucose homeostasis and highlight their role in intestinal glucose absorption.

Leptin mutation and mycobacterial infection lead non-synergistically to a similar metabolic syndrome

IntroductionThe leptin signaling pathway plays an important role as a key regulator of glucose homeostasis, metabolism control and systemic inflammatory responses. However, the metabolic effects of leptin on infectious diseases, for example tuberculosis (TB), are still little known.ObjectivesIn this study, we aim to investigate the role of leptin on metabolism in the absence and presence of mycobacterial infection in zebrafish larvae and mice.MethodsMetabolites in entire zebrafish larvae and the blood of mice were studied using high-resolution magic-angle-spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy and mass spectrometry, respectively. For transcriptome studies of zebrafish larvae, deep RNA sequencing was used.ResultsThe results show that leptin mutation leads to a similar metabolic syndrome as caused by mycobacterial infection in the two species, characterized by the decrease of 11 amine metabolites. In both species, this metabolic syndrome was not aggravated further when the leptin mutant was infected by mycobacteria. Therefore, we conclude that leptin and mycobacterial infection are both impacting metabolism non-synergistically. In addition, we studied the transcriptomes of lepbibl54 mutant zebrafish larvae and wild type (WT) siblings after mycobacterial infection. These studies showed that mycobacteria induced a very distinct transcriptome signature in the lepbibl54 mutant zebrafish compared to WT sibling control larvae. Furthermore, lepbibl55 Tg (pck1:luc1) zebrafish line was constructed and confirmed this difference in transcriptional responses.ConclusionsLeptin mutation and TB lead non-synergistically to a similar metabolic syndrome. Moreover, different transcriptomic responses in the lepbibl54 mutant and TB can lead to the similar metabolic end states.

Glucocorticoid signaling in pancreatic islets modulates gene regulatory programs and genetic risk of type 2 diabetes.

Glucocorticoids are key regulators of glucose homeostasis and pancreatic islet function, but the gene regulatory programs driving responses to glucocorticoid signaling in islets and the contribution of these programs to diabetes risk are unknown. In this study we used ATAC-seq and RNA-seq to map chromatin accessibility and gene expression from eleven primary human islet samples cultured in vitro with the glucocorticoid dexamethasone at multiple doses and durations. We identified thousands of accessible chromatin sites and genes with significant changes in activity in response to glucocorticoids. Chromatin sites up-regulated in glucocorticoid signaling were prominently enriched for glucocorticoid receptor binding sites and up-regulated genes were enriched for ion transport and lipid metabolism, whereas down-regulated chromatin sites and genes were enriched for inflammatory, stress response and proliferative processes. Genetic variants associated with glucose levels and T2D risk were enriched in glucocorticoid-responsive chromatin sites, including fine-mapped variants at 51 known signals. Among fine-mapped variants in glucocorticoid-responsive chromatin, a likely casual variant at the 2p21 locus had glucocorticoid-dependent allelic effects on beta cell enhancer activity and affected SIX2 and SIX3 expression. Our results provide a comprehensive map of islet regulatory programs in response to glucocorticoids through which we uncover a role for islet glucocorticoid signaling in mediating genetic risk of T2D.

TGR5 Signaling in Hepatic Metabolic Health.

TGR5 is a G protein-coupled bile acid receptor that is increasingly recognized as a key regulator of glucose homeostasis. While the role of TGR5 signaling in immune cells, adipocytes and enteroendocrine L cells in metabolic regulation has been well described and extensively reviewed, the impact of TGR5-mediated effects on hepatic physiology and pathophysiology in metabolic regulation has received less attention. Recent studies suggest that TGR5 signaling contributes to improvements in hepatic insulin signaling and decreased hepatic inflammation, as well as metabolically beneficial improvements in bile acid profile. Additionally, TGR5 signaling has been associated with reduced hepatic steatosis and liver fibrosis, and improved liver function. Despite the beneficial effects of TGR5 signaling on metabolic health, TGR5-mediated gallstone formation and gallbladder filling complicate therapeutic targeting of TGR5 signaling. To this end, there is a growing need to identify cell type-specific effects of hepatic TGR5 signaling to begin to identify and target the downstream effectors of TGR5 signaling. Herein, we describe and integrate recent advances in our understanding of the impact of TGR5 signaling on liver physiology and how its effects on the liver integrate more broadly with whole body glucose regulation.

Compound 18 Improves Glucose Tolerance in a Hepatocyte TGR5-dependent Manner in Mice.

The bile acid receptor, TGR5, is a key regulator of glucose homeostasis, but the mechanisms by which TGR5 signaling improves glucose regulation are incompletely defined. In particular, TGR5 has an increasingly appreciated role in liver physiology and pathobiology; however, whether TGR5 signaling within the liver contributes to its glucoregulatory effects is unknown. Therefore, we investigated the role of hepatocyte TGR5 signaling on glucose regulation using a hepatocyte-specific TGR5 knockout mouse model. Hepatocyte-specific Tgr5Hep+/+ and Tgr5Hep−/− mice were fed a high fat diet (HFD) for 7 weeks and then orally gavaged with three doses of a highly potent, TGR5-specific agonist, Compound 18 (10 mg/kg), or vehicle, over 72 h and underwent an oral glucose tolerance test (OGTT) after the last dose. Herein, we report that TGR5 mRNA and protein is present in mouse hepatocytes. Cumulative food intake, body weight, and adiposity do not differ between Tgr5Hep+/+ and Tgr5Hep−/− mice with or without treatment with Compound 18. However, administration of Compound 18 improves glucose tolerance in Tgr5HEP+/+ mice, but not in Tgr5Hep−/− mice. Further, this effect occurred independent of body weight and GLP-1 secretion. Together, these data demonstrate that TGR5 is expressed in hepatocytes, where it functions as a key regulator of whole-body glucose homeostasis.

Leptin is a key regulator of glucose homeostasis in obesity

Leptin is a key regulator of glucose homeostasis in obesity

Melatonin Signaling a Key Regulator of Glucose Homeostasis and Energy Metabolism.

Melatonin, a hormone synthesized by both the pineal gland and retina, functions as an important modulator of a number of physiological functions. In addition to its rather well-established roles in the regulation of circadian rhythms, sleep, and reproduction, melatonin has also been identified as an important regulator of glucose metabolism. Recent genomic studies have also shown that disruption of melatonin receptors signaling may contribute to the pathogenesis of type 2 diabetes, although the exact mechanisms underlying its action remain unclear. Additionally, a large number of animal studies have highlighted a role for melatonin in the regulation of both glucose metabolism and energy balance. This review summarizes the current knowledge on the role that melatonin and its associated receptors play in the regulation of metabolism.

Neuropeptide 26RFa (QRFP) is a key regulator of glucose homeostasis and its activity is markedly altered in obese/hyperglycemic mice.

Recent studies have shown that the hypothalamic neuropeptide 26RFa regulates glucose homeostasis by acting as an incretin and increasing insulin sensitivity. In this study, we further characterized the role of the 26RFa/GPR103 peptidergic system in the global regulation of glucose homeostasis using a 26RFa receptor antagonist and also assessed whether a dysfunction of the 26RFa/GPR103 system occurs in obese hyperglycemic mice. First, we demonstrate that administration of the GPR103 antagonist reduces the global glucose-induced incretin effect and insulin sensitivity whereas, conversely, administration of exogenous 26RFa attenuates glucose-induced hyperglycemia. Using a mouse model of high-fat diet-induced obesity and hyperglycemia, we found a loss of the antihyperglcemic effect and insulinotropic activity of 26RFa, accompanied with a marked reduction of its insulin-sensitive effect. Interestingly, this resistance to 26RFa is associated with a downregulation of the 26RFa receptor in the pancreatic islets, and insulin target tissues. Finally, we observed that the production and release kinetics of 26RFa after an oral glucose challenge is profoundly altered in the high-fat mice. Altogether, the present findings support the view that 26RFa is a key regulator of glucose homeostasis whose activity is markedly altered under obese/hyperglycemic conditions.

Recent Updates on Glucokinase Activators and Glucokinase Regulatory Protein Disrupters for the Treatment of Type 2 Diabetes Mellitus.

The impairment of glucose metabolism leads to hyperglycemia and type-2 diabetes mellitus. Glucokinase enzyme is the key regulator of glucose homeostasis that catalyzes the conversion of glucose to glucose-6-phosphate in liver and pancreatic cells. In hepatocytes, GK controls the glucose uptake and glycogen synthesis. The action of liver GK is controlled by Glucokinase Regulatory Protein (GKRP) partially. In fasting conditions the GKRP binds with GK and inactivate it from carbohydrate metabolism and serve as new target for treatment of diabetes mellitus. However, the GK activators as potential antidiabetic agents but results in increased risks of hypoglycemia. The allosteric inhibitors of the GK-GKRP interaction are coming as alternative agents that can mitigate the risk associated with GK activators. This review discusses the recent advances and current status of potential molecules targeted to GK activators and GK-GKRP disrupters.

Role of ROCK1 in Pancreatic ß Cells

Insulin signaling in pancreatic β-cell is critical for normal insulin secretion. ROCK1 plays an important role in the regulation of insulin and leptin signaling in the context of glucose and energy metabolism. However, the role of ROCK1 in pancreatic β-cell remains unknown. The current study was to determine whether deleting ROCK1 from β-cell affects insulin secretion and glucose metabolism in mice and cultured cell lines. Here we show that β-cell-specific deletion of ROCK1 results in a significant decrease insulin secretion in mice fed a normal chow diet, leading to hyperglycemia. These effects were independent of changes in adiposity. Consistent with this, in vitro studies with INS-1 and MIN6 cells indicated that inhibition of ROCK1 decreased insulin secretion in response to glucose without changes in β-cell proliferation and apoptosis. In addition, β-cell-ROCK1 deficient mice displayed glucose intolerance, as evidenced by the fact that the area under the glucose curve was increased 53% in β-cell-ROCK1 deficient mice compared with control mice. However, neither body weight, food intake nor insulin sensitivity was changed in theses mice. Upon insulin stimulation, proximal insulin signaling components, including p-IRS2, p-PI3K and p-Akt were impaired when ROCK1 expression was inhibited in INS-1 cells, suggesting a role for ROCK1 in insulin signaling. These data indicate that activation of ROCK1 in pancreatic β-cell is required for the maintenance of normal insulin secretion. Thus, pancreatic ROCK1 might be a key regulator of glucose homeostasis. Disclosure B. Sung: None. K. Hur: None. J. Kim: None. Y. Kim: None.M. Lee: None.

Intestinal bile acid receptors are key regulators of glucose homeostasis.

In addition to their well-known function as dietary lipid detergents, bile acids have emerged as important signalling molecules that regulate energy homeostasis. Recent studies have highlighted that disrupted bile acid metabolism is associated with metabolism disorders such as dyslipidaemia, intestinal chronic inflammatory diseases and obesity. In particular, type 2 diabetes (T2D) is associated with quantitative and qualitative modifications in bile acid metabolism. Bile acids bind and modulate the activity of transmembrane and nuclear receptors (NR). Among these receptors, the G-protein-coupled bile acid receptor 1 (TGR5) and the NR farnesoid X receptor (FXR) are implicated in the regulation of bile acid, lipid, glucose and energy homeostasis. The role of these receptors in the intestine in energy metabolism regulation has been recently highlighted. More precisely, recent studies have shown that FXR is important for glucose homeostasis in particular in metabolic disorders such as T2D and obesity. This review highlights the growing importance of the bile acid receptors TGR5 and FXR in the intestine as key regulators of glucose metabolism and their potential as therapeutic targets.

Role of Melatonin, Galanin, and RFamide Neuropeptides QRFP26 and QRFP43 in the Neuroendocrine Control of Pancreatic β-Cell Function

Glucose homeostasis is finely regulated by a number of hormones and peptides released mainly from the brain, gastrointestinal tract, and muscle, regulating pancreatic secretion through cellular receptors and their signal transduction cascades. The endocrine function of the pancreas is controlled by islets within the exocrine pancreatic tissue that release hormones like insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin. Moreover, both exocrine and endocrine pancreatic functions are regulated by a variety of hormonal and neural mechanisms, such as ghrelin, glucagon-like peptide, glucose-dependent insulinotropic polypeptide, or the inhibitory peptide somatostatin. In this review, we describe the role of neurohormones that have been less characterized compared to others, on the regulation of insulin secretion. In particular, we will focus on melatonin, galanin, and RFamide neuropeptides QRFP26 and QRFP43, which display either insulinotropic or insulinostatic effects. In fact, in addition to other hormones, amino acids, cytokines, and a variety of proteins, brain-derived hormones are now considered as key regulators of glucose homeostasis, representing potential therapeutic targets for the treatment of diabetes and obesity.

TCF7L2 involvement in estradiol- and progesterone-modulated islet and hepatic glucose homeostasis.

To evaluate the role of TCF7L2, a key regulator of glucose homeostasis, in estradiol (E2) and progesterone (P4)-modulated glucose metabolism, mouse insulinoma cells (MIN6) and human liver cancer cells (hepG2 and HUH7) were treated with physiological concentrations of E2 or P4 in the up- and down-regulation of TCF7L2. Insulin/proinsulin secretion was measured in MIN6 cells, while glucose uptake and production were evaluated in liver cancer cells. E2 increased insulin/proinsulin secretion under both basal and stimulated conditions, whereas P4 increased insulin/proinsulin secretion only under glucose-stimulated conditions. An antagonistic effect, possibly concentration-dependent, of E2 and P4 on the regulation of islet glucose metabolism was observed. After E2 or P4 treatment, secretion of insulin/proinsulin was positively correlated with TCF7L2 protein expression. When TCF7L2 was silenced, E2- or P4-promoted insulin/proinsulin secretion was significantly weakened. Under glucotoxicity conditions, overexpression of TCF7L2 increased insulin secretion and processing. In liver cancer cells, E2 or P4 exposure elevated TCF7L2 expression, enhanced the activity of insulin signaling (pAKT/pGSK), reduced PEPCK expression, subsequently increased insulin-stimulated glucose uptake, and decreased glucose production. Silencing TCF7L2 eliminated effects of E2 or P4. In conclusion, TCF7L2 regulates E2- or P4-modulated islet and hepatic glucose metabolism. The results have implications for glucose homeostasis in pregnancy.

Multiplexed Quantification of Proglucagon-Derived Peptides by Immunoaffinity Enrichment and Tandem Mass Spectrometry after a Meal Tolerance Test.

Proglucagon-derived peptides (PGDPs), which include glucagon-like peptide (GLP)-1, glucagon, and oxyntomodulin, are key regulators of glucose homeostasis and satiety. These peptide hormones are typically measured with immuno-based assays (e.g., ELISA, RIA), which often suffer from issues of selectivity. We developed a multiplexed assay for measuring PGDPs including GLP-1 (7-36) amide, GLP-1 (9-36) amide, glucagon, and oxyntomodulin by mass spectrometry and used this assay to examine the effect of a meal tolerance test on circulating concentrations of these hormones. Participants fasted overnight and were either given a meal (n = 8) or continued to fast (n = 4), with multiple blood collections over the course of 3 h. Plasma samples were analyzed by microflow immunoaffinity (IA)-LC-MS/MS with an isotope dilution strategy. Assay performance characteristics were examined and established during analytical validation for all peptides. Intra- and interassay imprecision were found to be 2.2%-10.7% and 6.8%-22.5%, respectively. Spike recovery was >76%, and dilution linearity was established up to a 16-fold dilution. Immediately after the meal tolerance test, GLP-1 and oxyntomodulin concentrations increased and had an almost identical temporal relationship, and glucagon concentrations increased with a slight delay. IA-LC-MS/MS was used for the simultaneous and selective measurement of PGDPs. This work includes the first indication of the physiological concentrations and modulation of oxyntomodulin after a meal.

Utilization of the Zucker Diabetic Fatty (ZDF) Rat Model for Investigating Hypoglycemia-related Toxicities.

Glucokinase (GK) catalyzes the initial step in glycolysis and is a key regulator of glucose homeostasis. Therefore, glucokinase activators (GKa) have potential benefit in treating type 2 diabetes. Administration of a Bristol-Myers Squibb GKa (BMS-820132) to healthy euglycemic Sprague-Dawley (SD) rats and beagle dogs in 1 mo toxicology studies resulted in marked and extended hypoglycemia with associated clinical signs of toxicity and degenerative histopathological changes in the stomach, sciatic nerve, myocardium, and skeletal muscles at exposures comparable to those expected at therapeutic clinical exposures. To investigate whether these adverse effects were secondary to exaggerated pharmacology (prolonged hypoglycemia), BMS-820132 was administered daily to male Zucker diabetic fatty (ZDF) rats for 1 mo. ZDF rats are markedly hyperglycemic and insulin resistant. BMS-820132 did not induce hypoglycemia, clinical signs of hypoglycemia, or any of the histopathologic adverse effects observed in the 1 mo toxicology studies at exposures that exceeded those observed in SD rats and dogs. This indicates that the toxicity observed in euglycemic animals was secondary to the exaggerated pharmacology of potent GK activation. This study indicates that ZDF rats, with conventional toxicity studies, are a useful disease model for testing antidiabetic agents and determining toxicities that are independent of prolonged hypoglycemia.