Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals.
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ABSTRACT:
SUBMITTER: McCreight LJ
PROVIDER: S-EPMC6946719 | biostudies-literature | 2020 Feb
REPOSITORIES: biostudies-literature
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Metformin increases fasting glucose clearance and endogenous glucose production in non-diabetic individuals.
McCreight Laura J LJ Mari Andrea A Coppin Lucy L Jackson Nicola N Umpleby A Margot AM Pearson Ewan R ER
Diabetologia 20191122 2
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Project description:Background/aimsFasting plasma glucose (FPG) levels correlate with cardiovascular disease and mortality in both diabetic and non-diabetic subjects. G6PC2 encodes a pancreatic islet-specific glucose-6-phosphatase-related protein and G6pc2-null mice were reported to exhibit decreased blood glucose levels. Two recent genome-wide association studies have implicated a role for G6PC2 in regulation of FPGlevels in the general European population and reported the strongest association with the rs560887 SNP. The purpose of this study was to replicate this association in our independent epidemiological samples.MethodsDNA samples from non-Hispanic white Americans (NHWs; n = 623), Hispanic Americans (n = 410) and black Africans (n = 787) were genotyped for rs560887 using TaqMan allelic discrimination.ResultsWhile no minor allele A of rs560887 was observed among blacks, its frequency was 33% in NHWs and 17.5% in Hispanics. The rs560887 minor allele was associated with reduced FPG levels in non-diabetic NHWs (p = 0.002 under an additive model). A similar trend of association was observed in non-diabetic Hispanics (p = 0.076 under a dominant model), which was more pronounced in normoglycemic subjects (p = 0.036).ConclusionsOur results independently confirm the robust association of G6PC2/rs560887 with FPG levels in non-diabetic NHWs. The observed evidence for association in Hispanics warrants further studies in larger samples.
| S-EPMC2855271 | biostudies-literature
Project description:Type 2 diabetes (T2D) affects the health of millions of people worldwide. The identification of genetic determinants associated with changes in glycemia over time might illuminate biological features that precede the development of T2D. Here we conducted a genome-wide association study of longitudinal fasting glucose changes in up to 13,807 non-diabetic individuals of European descent from nine cohorts. Fasting glucose change over time was defined as the slope of the line defined by multiple fasting glucose measurements obtained over up to 14 years of observation. We tested for associations of genetic variants with inverse-normal transformed fasting glucose change over time adjusting for age at baseline, sex, and principal components of genetic variation. We found no genome-wide significant association (P < 5 × 10-8) with fasting glucose change over time. Seven loci previously associated with T2D, fasting glucose or HbA1c were nominally (P < 0.05) associated with fasting glucose change over time. Limited power influences unambiguous interpretation, but these data suggest that genetic effects on fasting glucose change over time are likely to be small. A public version of the data provides a genomic resource to combine with future studies to evaluate shared genetic links with T2D and other metabolic risk traits.
| S-EPMC6602949 | biostudies-literature
Project description:Aims/hypothesisReal-life glycaemic profiles of healthy individuals are poorly studied. Our aim was to analyse to what extent individuals without diabetes exceed OGTT thresholds for impaired glucose tolerance (IGT) and diabetes.MethodsIn the A1C-Derived Average Glucose (ADAG) study, 80 participants without diabetes completed an intensive glucose monitoring period of 12 weeks. From these data, we calculated the average 24 h glucose exposure as time spent above different plasma glucose thresholds. We also derived indices of postprandial glucose levels, glucose variability and HbA(1c).ResultsWe found that 93% of participants reached glucose concentrations above the IGT threshold of 7.8 mmol/l and spent a median of 26 min/day above this level during continuous glucose monitoring. Eight individuals (10%) spent more than 2 h in the IGT range. They had higher HbA(1c), fasting plasma glucose (FPG), age and BMI than those who did not. Seven participants (9%) reached glucose concentrations above 11.1 mmol/l during monitoring.Conclusions/interpretationEven though the non-diabetic individuals monitored in the ADAG study were selected on the basis of a very low level of baseline FPG, 10% of these spent a considerable amount of time at glucose levels considered to be 'prediabetic' or indicating IGT. This highlights the fact that exposure to moderately elevated glucose levels remains under-appreciated when individuals are classified on the basis of isolated glucose measurements.
| S-EPMC2892065 | biostudies-literature
Project description:ObjectiveThe respective contributions to endogenous glucose production (EGP) of the liver, kidney and intestine vary during fasting. We previously reported that the deficiency in either hepatic or intestinal gluconeogenesis modulates the repartition of EGP via glucagon secretion (humoral factor) and gut-brain-liver axis (neural factor), respectively. Considering renal gluconeogenesis reportedly accounted for approximately 50% of EGP during fasting, we examined whether a reduction in renal gluconeogenesis could promote alterations in the repartition of EGP in this situation.MethodsWe studied mice whose glucose-6-phosphatase (G6Pase) catalytic subunit (G6PC) is specifically knocked down in the kidneys (K-G6pc-/- mice) during fasting. We also examined the additional effects of intestinal G6pc deletion, renal denervation and vitamin D administration on the altered glucose metabolism in K-G6pc-/- mice.ResultsCompared with WT mice, K-G6pc-/- mice exhibited (1) lower glycemia, (2) enhanced intestinal but not hepatic G6Pase activity, (3) enhanced hepatic glucokinase (GK encoded by Gck) activity, (4) increased hepatic glucose-6-phosphate and (5) hepatic glycogen spared from exhaustion during fasting. Increased hepatic Gck expression in the post-absorptive state could be dependent on the enhancement of insulin signal (AKT phosphorylation) in K-G6pc-/- mice. In contrast, the increase in hepatic GK activity was not observed in mice with both kidney- and intestine-knockout (KI-G6pc-/- mice). Hepatic Gck gene expression and hepatic AKT phosphorylation were reduced in KI-G6pc-/- mice. Renal denervation by capsaicin did not induce any effect on glucose metabolism in K-G6pc-/- mice. Plasma level of 1,25 (OH)2 D3, an active form of vitamin D, was decreased in K-G6pc-/- mice. Interestingly, the administration of 1,25 (OH)2 D3 prevented the enhancement of intestinal gluconeogenesis and hepatic GK activity and blocked the accumulation of hepatic glycogen otherwise observed in K-G6pc-/- mice during fasting.ConclusionsA diminution in renal gluconeogenesis that is accompanied by a decrease in blood vitamin D promotes a novel repartition of EGP among glucose producing organs during fasting, featured by increased intestinal gluconeogenesis that leads to sparing glycogen stores in the liver. Our data suggest a possible involvement of a crosstalk between the kidneys and intestine (via the vitamin D system) and the intestine and liver (via a neural gut-brain axis), which might take place in the situations of deficient renal glucose production, such as chronic kidney disease.
| S-EPMC6157617 | biostudies-literature
Project description:GPR40 (FFA1) is a fatty acid receptor whose activation results in potent glucose lowering and insulinotropic effects in vivo. Several reports illustrate that GPR40 agonists exert glucose lowering in diabetic humans. To assess the mechanisms by which GPR40 partial agonists improve glucose homeostasis, we evaluated the effects of MK-2305, a potent and selective partial GPR40 agonist, in diabetic Goto Kakizaki rats. MK-2305 decreased fasting glucose after acute and chronic treatment. MK-2305-mediated changes in glucose were coupled with increases in plasma insulin during hyperglycemia and glucose challenges but not during fasting, when glucose was normalized. To determine the mechanism(s) mediating these changes in glucose metabolism, we measured the absolute contribution of precursors to glucose production in the presence or absence of MK-2305. MK-2305 treatment resulted in decreased endogenous glucose production (EGP) driven primarily through changes in gluconeogenesis from substrates entering at the TCA cycle. The decrease in EGP was not likely due to a direct effect on the liver, as isolated perfused liver studies showed no effect of MK-2305 ex vivo and GPR40 is not expressed in the liver. Taken together, our results suggest MK-2305 treatment increases glucose stimulated insulin secretion (GSIS), resulting in changes to hepatic substrate handling that improve glucose homeostasis in the diabetic state. Importantly, these data extend our understanding of the underlying mechanisms by which GPR40 partial agonists reduce hyperglycemia.
| S-EPMC5441580 | biostudies-literature
Project description:BackgroundCognitive dysfunction has been recognized as a diabetes-related complication. Whether hyperglycemia or elevated fasting glucose are associated with cognitive decline remains controversial. We aimed to investigate the relationship between fasting glucose levels and cognitive function in diabetic and non-diabetic individuals.MethodsParticipants were Japanese diabetic (n = 191) and non-diabetic (n = 616) men, aged 46-81 years, from 2010-2014. Blood samples were taken after a 12 h fast. The Cognitive Ability Screening Instrument (CASI), with a maximum score of 100, was used for cognitive assessment. Cognitive domains of CASI were also investigated. Fractional logit regression with covariate adjustment for potential confounders was used to model cross-sectional relationships between fasting blood glucose and CASI score.ResultsFor diabetic individuals, CASI score was 0.38 (95% confidence interval: 0.66-0.12) lower per 1 mmol/L higher fasting glucose level. Short-term memory domain also exhibited an inverse association. For non-diabetic individuals, a reverse U-shaped relationship was observed between fasting glucose and cognitive function, identifying a threshold for highest cognitive performance of 91.8 CASI score at 3.97-6.20 mmol/L (71.5-111.6 mg/dL) fasting glucose. Language ability domain displayed a similar relationship with fasting glucose.ConclusionsElevated fasting glucose levels in diabetic men were associated with lower cognitive function, in which short-term memory was the main associated domain. Interestingly, in non-diabetic men, we identified a threshold for the inverse relationship of elevated fasting glucose with cognitive function. Contrastingly to diabetic men, language ability was the main associated cognitive domain among non-diabetic men.
| S-EPMC7025918 | biostudies-literature
Project description:BackgroundTriple tracer meal experiments used to investigate organ glucose-insulin dynamics, such as endogenous glucose production (EGP) of the liver are labor intensive and expensive. A procedure was developed to obtain individual liver related parameters to describe EGP dynamics without the need for tracers.ResultsThe development used an existing formula describing the EGP dynamics comprising 4 parameters defined from glucose, insulin and C-peptide dynamics arising from triple meal studies. The method employs a set of partial differential equations in order to estimate the parameters for EGP dynamics. Tracer-derived and simulated data sets were used to develop and test the procedure. The predicted EGP dynamics showed an overall mean R 2 of 0.91.ConclusionsIn summary, a method was developed for predicting the hepatic EGP dynamics for healthy, pre-diabetic, and type 2 diabetic individuals without applying tracer experiments.
| S-EPMC7422590 | biostudies-literature
Project description:IntroductionPrevious studies based on a single measure of fasting plasma glucose (FPG) showed an inconsistent conclusion about the association between FPG and osteoporosis risk. Not accounting for time-varying and cumulative average of FPG over time could bias the true relation between FPG and osteoporosis. Our study aims to investigate the association between the trajectories of FPG and osteoporosis risk for non-diabetic and diabetic populations.MethodsA total of 18,313 participants who attended physical examinations during 2008-2018 were included. They were free of osteoporosis at their first physical examination and followed until their last physical examination before December 31, 2018. We recorded their incidence of osteoporosis and at least three FPG values during follow-up. Their longitudinal FPG trajectories were identified by the latent class growth analysis model based on the changes in FPG. Multivariable logistic regression models were used to analyze the association between the trajectories of FPG and osteoporosis diagnosed in the follow-up physical examination in both non-diabetics and diabetics.ResultsThere were 752 incident osteoporosis among 16,966 non-diabetic participants, and 57 incident osteoporosis among 1,347 diabetic participants. Among non-diabetics, the elevated-increasing FPG trajectory was negatively associated with osteoporosis risk in women (odds ratio (OR), 0.62; 95% confidence interval (CI), 0.43-0.88). Premenopausal women with elevated-increasing FPG trajectory had lower osteoporosis risk than those women with normal-stable FPG trajectory (OR, 0.41; 95% CI, 0.20-0.88), while this association was insignificant in postmenopausal women. Among diabetics, those whose longitudinal FPG is kept at a very high level had the highest risk of osteoporosis (OR, 3.09; 95% CI, 1.16-8.22), whereas those whose FPG starts with the high level and keeps on increasing did not exhibit a significantly increased risk (OR, 1.75; 95% CI, 0.81-3.76) compared with those who keep stable moderate-high level of FPG, except in men (OR, 2.49; 95% CI, 1.02-6.12).ConclusionDistinct trajectories of FPG are associated with differential risk of osteoporosis in non-diabetic and diabetic populations. Controlling a proper FPG level in different populations is necessary for osteoporosis prevention.
| S-EPMC9679646 | biostudies-literature
Project description:Aims/hypothesisTo test among diabetes-free urban community-dwelling adults the hypothesis that the proportion of African genetic ancestry is positively associated with glycaemia, after accounting for other continental ancestry proportions, BMI and socioeconomic status (SES).MethodsThe Boston Area Community Health cohort is a multi-stage 1:1:1 stratified random sample of self-identified African-American, Hispanic and white adults from three Boston inner city areas. We measured 62 ancestry informative markers, fasting glucose (FG), HbA1c, BMI and SES (income, education, occupation and insurance status) and analysed 1,387 eligible individuals (379 African-American, 411 Hispanic, 597 white) without clinical or biochemical evidence of diabetes. We used three-heritage multinomial linear regression models to test the association of FG or HbA1c with genetic ancestry proportion adjusted for: (1) age and sex; (2) age, sex and BMI; and (3) age, sex, BMI and SES.ResultsMean age- and sex-adjusted FG levels were 5.73 and 5.54 mmol/l among those with 100% African or European ancestry, respectively. Using per cent European ancestry as the referent, each 1% increase in African ancestry proportion was associated with an age- and sex-adjusted FG increase of 0.0019 mmol/l (p = 0.01). In the BMI- and SES-adjusted model the slope was 0.0019 (p = 0.02). Analysis of HbA1c gave similar results.Conclusions/interpretationA greater proportion of African genetic ancestry is independently associated with higher FG levels in a non-diabetic community-based cohort, even accounting for other ancestry proportions, obesity and SES. The results suggest that differences between African-Americans and whites in type 2 diabetes risk may include genetically mediated differences in glucose homeostasis.
| S-EPMC5424892 | biostudies-literature
Project description:BackgroundAdverse effects of metformin are primarily related to gastrointestinal (GI) intolerance that could limit titration to an efficacious dose or cause discontinuation of the medication. Because some metformin side effects may be attributable to shifts in the GI microbiome, we tested whether a GI microbiome modulator (GIMM) used in combination with metformin would ameliorate the GI symptoms.MethodsA 2-period crossover study design was used with 2 treatment sequences, either placebo in period 1 followed by GIMM in period 2 or vice versa. Study periods lasted for 2 weeks, with a 2-week washout period between. During the first week, type 2 diabetes patients (T2D) who experienced metformin GI intolerance took 500 mg metformin along with their assigned NM504 (GIMM) or placebo treatment with breakfast and with dinner. In the second week, the 10 subjects took 500 mg metformin (t.i.d.), with GIMM or placebo consumed with the first and third daily metformin doses. Subjects were permitted to discontinue metformin dosing if it became intolerable.ResultsThe combination of metformin and GIMM treatment produced a significantly better tolerance score to metformin than the placebo combination (6.78 ± 0.65 [mean ± SEM] versus 4.45 ± 0.69, P = .0006). Mean fasting glucose levels were significantly (P < .02) lower with the metformin-GIMM combination (121.3 ± 7.8 mg/dl) than with metformin-placebo (151.9 ± 7.8 mg/dl).ConclusionCombining a GI microbiome modulator with metformin might allow the greater use of metformin in T2D patients and improve treatment of the disease.
| S-EPMC4525649 | biostudies-literature