Gluconeogenesis is a critical biosynthetic process that helps maintain whole-body glucose homeostasis and becomes altered in certain medical diseases. We review gluconeogenic flux in various medical diseases, including common metabolic disorders, hormonal imbalances, specific inborn genetic errors, and cancer. We discuss how the altered gluconeogenic activity contributes to disease pathogenesis using data from experiments using isotopic tracer and spectroscopy methodologies. These in vitro, animal, and human studies provide insights into the changes in circulating levels of available gluconeogenesis substrates and the efficiency of converting those substrates to glucose by gluconeogenic organs. We highlight ongoing knowledge gaps, discuss emerging research areas, and suggest future investigations. A better understanding of altered gluconeogenesis flux may ultimately identify novel and targeted treatment strategies for such diseases.

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease, has become a silent worldwide pandemic. The incidence of NAFLD correlates with the rise in obesity, type 2 diabetes, and metabolic syndrome. A hallmark featureof NAFLD is excessive hepatic fat accumulation or steatosis, due to dysregulated hepatic fat metabolism, which can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Currently, there are no approved pharmacotherapies to treat this disease. Here, we have found that activation of the kisspeptin 1 receptor (KISS1R) signaling pathway has therapeutic effects in NAFLD. Using high-fat diet–fed mice, we demonstrated that a deletion of hepatic Kiss1r exacerbated hepatic steatosis. In contrast, enhanced stimulation of KISS1R protected against steatosis in wild-type C57BL/6J mice and decreased fibrosis using a diet-induced mouse model of NASH. Mechanistically, we found that hepatic KISS1R signaling activates the master energy regulator, AMPK, to thereby decrease lipogenesis and progression to NASH. In patients with NAFLD and in high-fat diet–fed mice, hepatic KISS1/KISS1R expression and plasma kisspeptin levels were elevated, suggesting a compensatory mechanism to reduce triglyceride synthesis. These findings establish KISS1R as a therapeutic target to treat NASH.

This study compares blood pressure and heart rate responses with graded, incremental exercise between morning and intermediate chronotype adults with obesity. Herein, blood pressure responses to exercise were elevated in intermediate compared with morning chronotype, although V̇o_2max abolished this observation. However, heart rate responses to exercise were higher in intermediate vs. morning chronotypes independent of fitness. Collectively, this exercise hemodynamic response among intermediate chronotype may be related to reduced aerobic fitness, altered nitric oxide metabolism, and/or elevated aortic waveforms.

Glycerol can be metabolized to glucose via gluconeogenesis or lactate via glycolysis. It is unknown if glycerol is metabolized similarly in the portal and systemic circulations in humans. Eight metabolically healthy overnight-fasted individuals received equimolar amounts of ¹³C₃-glycerol orally and intravenously on two separate occasions with serial blood draws over four hours. Serum samples underwent liquid chromatography–mass spectrometry analysis. Oral ¹³C₃-glycerol administration led to higher average serum glucose enrichment than intravenous administration (5.02 ± 1.43 versus 4.07 ± 0.79%, p = 0.009). In contrast, intravenous ¹³C₃-glycerol administration yielded higher average serum lactate enrichment than oral administration (5.67 ± 0.80 versus 4.85 ± 1.30%, p = 0.032). Peak serum glucose enrichment was also higher with oral administration (9.37 ± 2.93 versus 7.12 ± 1.28%, p = 0.010). Glycerol metabolism across the portal and systemic circulations is not congruent. Orally administered labeled glycerol led to greater labeled glucose production, while intravenously administration yielded greater lactate production. These data support direct glycerol to lactate conversion in humans.

Glycerol kinase deficiency (GKD) is an X‐linked recessive disorder due to glycerol kinase (GK) gene mutations resulting in hyperglycerolermia, hyperglyceroluria, and “pseudohypertriglyceridemia.” In vivo glycerol metabolism has not been assessed in GKD. A 62‐year‐old man with suspected GKD and his extended family underwent whole exome sequencing and fasting blood work with two modes of lipid measurements: (1) standard lipase‐based methodology and (2) nuclear magnetic resonance (NMR). Two overnight fasted men with GKD and a heterozygote female carrier then underwent ¹³C₃‐glycerol infusion. Affected family members had a novel two‐nucleotide deletion in exon 5 of the GK gene (c.373_374del). Compared to their family members (n = 14), men with GKD (n = 5) had significantly lower total cholesterol levels (3.72 ± 0.70 vs. 4.77 ± 0.85 mmol/L, p = 0.024). Compared to NMR, lipase‐based assays overreported triglycerides (5.28 ± 1.38 vs. 0.81 ± 0.32, mmol/L, p < 0.001) and underreported low‐density lipoprotein cholesterol values (0.93 ± 0.23 vs. 2.18 ± 0.42 mmol/L, p = 0.001) in GKD. Men with GKD could not convert glycerol into glucose or triglycerides, which was preserved in the heterozygote carrier. Glycolytic metabolism of glycerol to lactate persisted in GKD, but it was reduced by a magnitude and, possibly, due to homologous glycerol kinases encoded by other genes. In summary, we report a novel GK pathogenic variant; affected men cannot convert circulating glycerol to glucose or triglycerides and have lower cholesterol levels. These results offer a human model for potentially targeting glycerol kinase to treat conditions associated with hyperglycemia and hyperlipidemia and warrant further investigation.