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Early-life programming of susceptibility to dysregulation of glucose metabolism and the development of Type 2 diabetes mellitus.

ABSTRACT: There is increasing epidemiological evidence in humans which associates low birthweight with later metabolic disorders, including insulin resistance and glucose intolerance. There is evidence that nutritional and hormonal factors (e.g. maternal protein restriction, exposure to excess maternal glucocorticoids) markedly influence intra-uterine growth and development. A picture is also emerging of the biochemical and physiological mechanisms that may underlie these effects. This review focuses on recent research directed towards understanding the molecular basis of the relationship between indices of poor early growth and the subsequent development of glucose intolerance and Type 2 diabetes mellitus using animal models that attempt to recreate the process of programming via an adverse intra-uterine or neonatal environment. Emphasis is on the chain of events and potential mechanisms by which adverse adaptations affect pancreatic-beta-cell insulin secretion and the sensitivity to insulin of key metabolic processes, including hepatic glucose production, skeletal-muscle glucose disposal and adipose-tissue lipolysis. Unravelling the molecular details involved in metabolic programming may provide new insights into the pathogenesis of impaired glucoregulation and Type 2 diabetes.

SUBMITTER: Holness MJ

PROVIDER: S-EPMC1221191 | biostudies-other | 2000 Aug

REPOSITORIES: biostudies-other

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Project description:Background Mechanistic studies suggest that aldosterone impairs glucose metabolism. We investigated the cross-sectional associations of aldosterone and plasma renin activity with fasting plasma glucose, insulin resistance ( IR ), β-cell function, and longitudinal association with incident diabetes mellitus among adults in MESA (the multiethnic study of atherosclerosis) prospective cohort study. Methods and Results Homeostatic model assessment of IR ( HOMA 2- IR ) and HOMA 2-β were used to estimate IR and β-cell function, respectively. Incident diabetes mellitus was defined as fasting plasma glucose ≥126 mg/dL or anti-diabetic medication use at follow-up. Linear regression was used to examine cross-sectional associations of aldosterone with fasting plasma glucose, HOMA 2- IR and HOMA 2-β; Cox regression was used to estimate hazard ratios ( HR ) for incident diabetes mellitus with multivariable adjustment. There were 116 cases of incident diabetes mellitus over 10.5 years among 1570 adults (44% non-Hispanic white, 13% Chinese American, 19% Black, 24% Hispanic American, mean age 64±10 years, 51% female). A 100% increase in log-aldosterone was associated with a 2.6 mg/dL higher fasting plasma glucose, 15% higher HOMA 2- IR and 6% higher HOMA 2-β ( P<0.01). A 1- SD increase in log-aldosterone was associated with a 44% higher risk of incident diabetes mellitus ( P<0.01) with the greatest increase of 142% ( P<0.01) observed in Chinese Americans ( P for interaction=0.09 versus other ethnicities). Similar cross-sectional findings for log-plasma renin activity existed, but log-plasma renin activity was not associated with incident diabetes mellitus after full adjustment. Conclusions Aldosterone is associated with glucose homeostasis and diabetes mellitus risk with graded associations among Chinese Americans and blacks, suggesting that pleiotropic effects of aldosterone may represent a modifiable mechanism in diabetes mellitus pathogenesis with potential racial/ethnic variation.

Project description:Elevated blood glucose levels during intensive care unit (ICU) stay, so-called stress hyperglycaemia (SH), is a common finding. Its relation with a future diabetes risk is unclear. Our objective was to determine the incidence of disturbed glucose metabolism (DGM) post ICU admission and to identify predictors for future diabetes risk with a focus on stress hyperglycaemia.This single center prospective cohort trial (DIAFIC trial) had a study period between September 2011 and March 2013, with follow-up until December 2013. The setting was a mixed medical/surgical ICU in a tertiary teaching hospital in Belgium. 338 patients without known diabetes mellitus were included for analysis. We assessed the level of glucose metabolism disturbance (as diagnosed with a 75 g oral glucose tolerance test (OGTT) and/or HbA1c level) eight months after ICU admission, and investigated possible predictors including stress hyperglycaemia.In total 246 patients (73 %) experienced stress hyperglycaemia during the ICU stay. Eight months post-ICU admission, 119 (35 %) subjects had a disturbed glucose metabolism, including 24 (7 %) patients who were diagnosed with diabetes mellitus. A disturbed glucose metabolism tended to be more prevalent in subjects who experienced stress hyperglycaemia during ICU stay as compared to those without stress hyperglycaemia (38 % vs. 28 %, P = 0.065). HbA1c on admission correlated with the degree of stress hyperglycaemia. A diabetes risk score (FINDRISC) (11.0 versus 9.5, P = 0.001), the SAPS3 score (median of 42 in both groups, P = 0.003) and daily caloric intake during ICU stay (197 vs. 222, P = 0.011) were independently associated with a disturbed glucose metabolism.Stress hyperglycaemia is frequent in non-diabetic patients and predicts a tendency towards disturbances in glucose metabolism and diabetes mellitus. Clinically relevant predictors of elevated risk included a high FINDRISC score and a high SAPS3 score. These predictors can provide an efficient, quick and inexpensive way to identify patients at risk for a disturbed glucose metabolism or diabetes, and could facilitate prevention and early treatment.At ClinicalTrials.gov NCT02180555 . Registered 1 July, 2014.

Project description:BackgroundGestational diabetes mellitus (GDM) is the most common complication during pregnancy, occurring under the combined action of environmental and genetic factors. Genetic variants of glucagon-like peptide-1 receptor (GLP-1R) have been reported to affect insulin secretion and susceptibility to type 2 diabetes. This study aimed to explore the role of GLP-1R polymorphisms in GDM and glucose metabolism.MethodsA two-center nested case‒control study was designed, including 200 pregnant women with GDM and 200 pregnant women without GDM genotyped for five tag SNPs of GLP-1R using Sanger sequencing. Logistic regression was used to evaluate the relationship between GLP-1R polymorphisms and GDM risk. Glucose and insulin concentrations were measured based upon the 75 g oral glucose tolerance test (OGTT). Beta cell function of different genotypes was estimated with the 60 min insulinogenic index (IGI60) and OGTT-derived disposition index (DI).ResultsMutant genotype AG + GG of tag SNP rs6458093 nominally increased GDM risk (p = 0.049), especially among subjects younger than 35 years (p = 0.024) and with BMI no less than 24 (p = 0.041), after adjusting for confounders. Meanwhile, compared with subjects with wild genotype AA, subjects with genotype AG + GG of rs6458093 also showed nominally significantly lower IGI60 (p = 0.032) and DI (p = 0.029), as well as significantly higher 75 g OGTT-based 1 h glucose load plasma glucose levels (p = 0.045). Moreover, the mutant heterozygous genotype GA of tag SNP rs3765467 nominally decreased GDM risk among subjects older than 35 years (p = 0.037) but showed no association with insulin secretion and glucose homeostasis.ConclusionsTag SNP rs6458093 of GLP-1R was nominally associated with increased GDM risk and affected beta cell function and postprandial glucose metabolism, while tag SNP rs3765467 of GLP-1R was nominally associated with decreased GDM risk, providing evidence for molecular markers and etiological study of GDM.

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Early-life programming of susceptibility to dysregulation of glucose metabolism and the development of Type 2 diabetes mellitus.

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