Use of 4β‐Hydroxycholesterol Plasma Concentrations as an Endogenous Biomarker of CYP3A Activity: Clinical Validation in Individuals With Type 2 Diabetes

Background: Animal experiments have suggested that exposure to persistent organic pollutants (POPs) may lead to increased risk of type 2 diabetes. Although recent human studies supported this hypothesis, evidence from prospective investigations is sparse. Objective: To examine the associations of plasma POP concentrations with risk of incident type 2 diabetes in a prospective setting among US women. Methods: Study population was comprised of participants from two independent nested case-control studies in the Nurses’ Health Study, in which major polychlorinated biphenyl (PCB 118, 138, 153, and 180), p-p'- dichlorodiphenyldichloroethylene (DDE), dichlorodiphenyltrichloroethane (DDT), and hexachlorobenzene (HCB) were measured. A non-parametric approach was used to derive standardized scores for plasma concentrations of lipid-adjusted POPs within each study to minimize between-study variation of the POP measurements. Risk of incident type 2 diabetes during the follow-up period (1990-2008) across the tertiles of the scores was examined. Results: Of 1,120 participants, we identified 48 incident type 2 diabetes cases. After adjusting for covariates assessed at blood draw in 1990, including smoking status, body mass index, and total fish intake, plasma HCB concentration was positively associated with type 2 diabetes risk: odds ratio (OR) (95% confidence interval [CI]) was 2.77 (1.17, 6.55, P for trend =0.022) comparing the highest vs. lowest tertile. Other POPs were not significantly associated with diabetes: the ORs (95% CI) were 1.10 (0.51, 2.34, P for trend =0.81) for p-p'-DDE, 0.93 (0.44, 1.95, P for trend =0.86) for DDT, and 0.88 (0.39, 1.97, P for trend =0.76) for sum of the 4 major PCBs, comparing the extreme tertiles. Conclusion: The significant association of plasma HCB concentration with diabetes risk supports a role of POP exposure in the etiology of type 2 diabetes. More prospective data are warranted to confirm these findings.

Download Full-text

Association of vitamin D3 and its metabolites in patients with and without type 2 diabetes and their relationship to diabetes complications

Therapeutic Advances in Chronic Disease ◽

10.1177/2040622320924159 ◽

2020 ◽

Vol 11 ◽

pp. 204062232092415

Author(s):

Alexandra E. Butler ◽

Soha R. Dargham ◽

Aishah Latif ◽

Haira R. Mokhtar ◽

Amal Robay ◽

...

Keyword(s):

Type 2 Diabetes ◽

Vitamin D ◽

Diabetes Complications ◽

Plasma Concentrations ◽

Vascular Complications ◽

Mass Spectrometry Analysis ◽

Cross Sectional ◽

Spectrometry Analysis ◽

Dihydroxyvitamin D

Background: Epidemiological studies have suggested that vitamin D deficiency is associated with the development of type 2 diabetes (T2DM) and is related to diabetes complications. This study was undertaken to determine the relationship between diabetes complications and cardiovascular risk factors with vitamin D3 and its metabolites: 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), 25-hydroxyvitamin D3 (25(OH)D3), 24,25-dihydroxyvitamin D3 (24,25(OH)2D3); and 25-hydroxy-3epi-vitamin D3 (3epi25(OH)D3). Methods: 750 Qatari subjects, 460 (61.3%) with and 290 (38.7%) without T2DM, who were not taking vitamin D3 supplements, participated in this cross-sectional, observational study. Plasma concentrations of vitamin D3 and its metabolites were measured by liquid chromatography tandem mass spectrometry analysis. Results: T2DM subjects had lower concentrations of all vitamin D3 metabolites ( p < 0.001) except 3epi25(OH)D3 ( p < 0.071). Males had higher concentrations of all vitamin D3 metabolites ( p < 0.001). In the T2DM subjects, lower 25(OH)D3 was associated with retinopathy ( p < 0.03) and dyslipidemia ( p < 0.04), but not neuropathy or vascular complications; lower 1,25(OH)2D3 was associated with hypertension ( p < 0.009), dyslipidemia ( p < 0.003) and retinopathy ( p < 0.006), and coronary artery disease ( p < 0.012), but not neuropathy; lower 24,25(OH)2D3 concentrations were associated with dyslipidemia alone ( p < 0.019); 3epi25(OH)D3 associated with diabetic neuropathy alone ( p < 0.029). In nondiabetics, 25(OH)D3, 1,25(OH)2D3 and 24,25(OH)2D3 were associated with dyslipidemia ( p < 0.001, p < 0.001, p < 0.015, respectively) and lower 1,25(OH)2D3 was associated with hypertension ( p < 0.001). Spearman’s correlation showed 1,25(OH)2D3 to be negatively correlated to age and diabetes duration. Conclusions: Different diabetes complications were associated with differing vitamin D parameters, with diabetic retinopathy related to lower 25(OH)D3 and 1,25(OH)2D3 levels, hypertension significantly associated with lower 1,25(OH)2D3, while dyslipidemia was associated with lower 25(OH)D3, 1,25(OH)2D3 and 24,25(OH)2D3. While 25(OH)D metabolites were lower in females, there was not an exaggeration in complications.

Download Full-text

Kringle IV Type 2, Not Low Lipoprotein(a), as a Cause of Diabetes: A Novel Genetic Approach Using SNPs Associated Selectively with Lipoprotein(a) Concentrations or with Kringle IV Type 2 Repeats

Clinical Chemistry ◽

10.1373/clinchem.2017.277103 ◽

2017 ◽

Vol 63 (12) ◽

pp. 1866-1876 ◽

Cited By ~ 14

Author(s):

Andra Tolbus ◽

Martin B Mortensen ◽

Sune F Nielsen ◽

Pia R Kamstrup ◽

Stig E Bojesen ◽

...

Keyword(s):

Type 2 Diabetes ◽

Odds Ratio ◽

Plasma Concentrations ◽

Nucleotide Polymorphisms ◽

Genetic Approach ◽

Lipoprotein A ◽

Heart Study ◽

Increased Risk ◽

Per Se

Abstract BACKGROUND Low plasma lipoprotein(a) concentrations are associated with type 2 diabetes. Whether this is due to low lipoprotein(a) concentrations per se or to a large number of kringle IV type 2 (KIV-2) repeats remains unclear. We therefore aimed to identify genetic variants associated selectively with lipoprotein(a) concentrations or with the number of KIV-2 repeats, to investigate which of these traits confer risk of diabetes. METHODS We genotyped 8411 individuals from the Copenhagen City Heart Study for 778 single-nucleotide polymorphisms (SNPs) in the proximity of the LPA gene, and examined the association of these SNPs with plasma concentrations of lipoprotein(a) and with KIV-2 number of repeats. SNPs that were selectively associated with lipoprotein(a) concentrations but not with KIV-2 number of repeats, or vice versa, were included in a Mendelian randomization study. RESULTS We identified 3 SNPs (rs12209517, rs12194138, and rs641990) that were associated selectively with lipoprotein(a) concentrations and 3 SNPs (rs1084651, rs9458009, and rs9365166) that were associated selectively with KIV-2 number of repeats. For SNPs selectively associated with lipoprotein(a) concentrations, an allele score of 4–6 vs 0–2 had an odds ratio for type 2 diabetes of 1.03 (95% CI, 0.86–1.23). In contrast, for SNPs selectively associated with KIV-2 number of repeats, an allele score of 4–6 vs 0–2 had an odds ratio for type 2 diabetes of 1.42 (95% CI, 1.17–1.69). CONCLUSIONS Using a novel genetic approach, our results indicate that it is a high number of KIV-2 repeats that are associated causally with increased risk of type 2 diabetes, and not low lipoprotein(a) concentrations per se. This is a reassuring finding for lipoprotein(a)-lowering therapies that do not increase the KIV-2 number of repeats.

Download Full-text

Plasma Amino Acids Metabolomics' Important in Glucose Management in Type 2 Diabetes

Frontiers in Pharmacology ◽

10.3389/fphar.2021.695418 ◽

2021 ◽

Vol 12 ◽

Author(s):

Abdelrahim Alqudah ◽

Mohammed Wedyan ◽

Esam Qnais ◽

Hassan Jawarneh ◽

Lana McClements

Keyword(s):

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Amino Acids ◽

Amino Acid ◽

Fasting Blood Glucose ◽

Plasma Concentrations ◽

Essential Amino Acids ◽

Amino Acid Profile ◽

Healthy Controls

The perturbation in plasma free amino acid metabolome has been observed previously in diabetes mellitus, and is associated with insulin resistance as well as the onset of cardiovascular disease in this population. In this study, we investigated, for the first time, changes in the amino acid profile in a group of people with and without type 2 diabetes (T2D) with normal BMI, from Jordan, who were only managed on metformin. Twenty one amino acids were evaluated in plasma samples from 124 people with T2D and 67 healthy controls, matched for age, gender and BMI, using amino acids analyser. Total amino acids, essential amino acids, non-essential amino acids and semi-essential amino acids were similar in T2D compared to healthy controls. Plasma concentrations of four essential amino acids were increased in the presence of T2D (Leucine, p < 0.01, Lysine, p < 0.001, Phenylalanine, p < 0.01, Tryptophan, p < 0.05). On the other hand, in relation to non-essential amino acids, Alanine and Serine were reduced in T2D (p < 0.01, p < 0.001, respectively), whereas Aspartate and Glutamate were increased in T2D compared to healthy controls (p < 0.001, p < 0.01, respectively). A semi-essential amino acid, Cystine, was also increased in T2D compared to healthy controls (p < 0.01). Citrulline, a metabolic indicator amino acid, demonstrated lower plasma concentration in T2D compared to healthy controls (p < 0.01). These amino acids were also correlated with fasting blood glucose and HbA1c (p < 0.05). Glutamate, glycine and arginine were correlated with the duration of metformin treatment (p < 0.05). No amino acid was correlated with lipid profiles. Disturbances in the metabolism of these amino acids are closely implicated in the pathogenesis of T2D and associated cardiovascular disease. Therefore, these perturbed amino acids could be explored as therapeutic targets to improve T2D management and prevent associated cardiovascular complications.

Download Full-text

Once daily versus twice daily Linagliptin effect on glycemic levels in type 2 diabetes mellitus- an observational study

International Journal of Research in Medical Sciences ◽

10.18203/2320-6012.ijrms20174567 ◽

2017 ◽

Vol 5 (10) ◽

pp. 4403

Author(s):

Riyaz Mohammed ◽

Mohammed Azfar Ali

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Observational Study ◽

Plasma Concentrations ◽

Fixed Dose ◽

Once Daily ◽

Group A ◽

Group B

Background: DPP-4 is widely distributed in endothelial cells, pancreas, uterus, liver, salivary glands, lymph node, spleen, and thymus. DPP-4 regulates glucagon-like peptide (GLP)-1, and glucose-dependent insulin tropic peptide (GIP) which leads to glucose homeostasis via enhancing insulin secretion and suppression of glucagon, which results in control of post-prandial and fasting hyperglycemia.Methods: These 40 patients who were enrolled as per the inclusion criteria of receiving metformin dosage of 2 gram per day in established type 2 diabetes mellitus patients with no comorbidities. these patients were divided randomly into two groups comprising of 20 patients each, group A received linagliptin 5 mg per day in addition to metformin 1gm twice daily whereas group B received linagliptin 5 mg per day in a fixed dose (Linagliptin + metformin) of 2.5/1000 twice daily.Results: In the present observational study, the mean age in group A was 46.7±9.4 compared to 51.65±9.9 in group B, p >0.05, mean BMI in group A was 27.8±1.1 compared to 27.28±0.93 in group B p >0.05, Mean FBS in group A was 157.9±24.1 compared to 146.2±21.8 in group B p >0.05, Mean PPBS in group A was 245.8±32.7 compared to 246.2±39.3 in group B p >0.05 and Mean HbA1c in group A was 7.67±0.58 compared to 7.6±0.5 in group B p >0.05. Group A patients were initiated on once daily linagliptin, there was a significant reduction in FBS, PPBS and HbA1c at the end of 6 months p <0.001. Similarly, Group B patients who were initiated on twice daily linagliptin also showed a significant reduction in FBS, PPBS and HbA1c at the end of 6 months p <0.001.Conclusions: The addition of linagliptin to metformin treatment was effective and well tolerated in patients with type 2 diabetes. Linagliptin add-on to metformin during the early course of treatment helps in delaying the exhaustion of pancreatic islet function. Plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4. The prolonged elimination phase does not contribute to the accumulation of the drug. Addition of linagliptin to metformin has shown a significant reduction in FBS, PPBS and HbA1c.

Download Full-text

Dietary Intakes and Circulating Concentrations of Branched-Chain Amino Acids in Relation to Incident Type 2 Diabetes Risk Among High-Risk Women with a History of Gestational Diabetes Mellitus

Clinical Chemistry ◽

10.1373/clinchem.2017.285841 ◽

2018 ◽

Vol 64 (8) ◽

pp. 1203-1210 ◽

Cited By ~ 17

Author(s):

Deirdre K Tobias ◽

Clary Clish ◽

Samia Mora ◽

Jun Li ◽

Liming Liang ◽

...

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

Amino Acids ◽

Gestational Diabetes ◽

Plasma Concentrations ◽

Branched Chain Amino Acids ◽

High Risk Women ◽

History Of ◽

Branched Chain

Abstract BACKGROUND Circulating branched-chain amino acids (BCAAs; isoleucine, leucine, valine) are consistently associated with increased type 2 diabetes (T2D) risk, but the relationship with dietary intake of BCAAs is less clear. METHODS The longitudinal Nurses' Health Study II cohort conducted a blood collection from 1996 to 1999. We profiled plasma metabolites among 172 incident T2D cases and 175 age-matched controls from women reporting a history of gestational diabetes before blood draw. We estimated dietary energy-adjusted BCAAs from food frequency questionnaires. We used conditional logistic regression models to estimate odds ratios (OR) and 95% CI of T2D risk across quartiles (Q1–Q4) of BCAAs, adjusting for age, body mass index (BMI), physical activity, family history, and other established risk factors. We also assessed joint exposure to below/above medians of diet and plasma concentrations, with lower diet/lower plasma as reference. RESULTS Dietary and plasma BCAA concentrations were positively associated with incident T2D (diet Q4 vs Q1 OR = 4.6, CI = 1.6, 13.4; plasma Q4 vs Q1 OR = 4.4, CI = 1.4, 13.4). Modeling the joint association indicated that higher diet BCAAs were associated with T2D when plasma concentrations were also higher (OR = 6.0, CI = 2.1, 17.2) but not when concentrations were lower (OR = 1.6, CI = 0.61, 4.1). Conversely, higher plasma BCAAs were associated with increased T2D for either lower or higher diet. CONCLUSIONS Independent of BMI and other risk factors, higher diet and plasma BCAA concentrations were associated with an increased incident T2D risk among high-risk women with a history of gestational diabetes, supporting impaired BCAA metabolism as conferring T2D risk.

Download Full-text

The Liver–α-Cell Axis and Type 2 Diabetes

Endocrine Reviews ◽

10.1210/er.2018-00251 ◽

2019 ◽

Vol 40 (5) ◽

pp. 1353-1366 ◽

Cited By ~ 19

Author(s):

Nicolai J Wewer Albrechtsen ◽

Jens Pedersen ◽

Katrine D Galsgaard ◽

Marie Winther-Sørensen ◽

Malte P Suppli ◽

...

Keyword(s):

Type 2 Diabetes ◽

Liver Disease ◽

Amino Acid ◽

Fatty Liver ◽

Hepatic Steatosis ◽

Fatty Liver Disease ◽

Metabolic Diseases ◽

Plasma Concentrations ◽

Amino Acid Turnover

Abstract Both type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) strongly associate with increasing body mass index, and together these metabolic diseases affect millions of individuals. In patients with T2D, increased secretion of glucagon (hyperglucagonemia) contributes to diabetic hyperglycemia as proven by the significant lowering of fasting plasma glucose levels following glucagon receptor antagonist administration. Emerging data now indicate that the elevated plasma concentrations of glucagon may also be associated with hepatic steatosis and not necessarily with the presence or absence of T2D. Thus, fatty liver disease, most often secondary to overeating, may result in impaired amino acid turnover, leading to increased plasma concentrations of certain glucagonotropic amino acids (e.g., alanine). This, in turn, causes increased glucagon secretion that may help to restore amino acid turnover and ureagenesis, but it may eventually also lead to increased hepatic glucose production, a hallmark of T2D. Early experimental findings support the hypothesis that hepatic steatosis impairs glucagon’s actions on amino acid turnover and ureagenesis. Hepatic steatosis also impairs hepatic insulin sensitivity and clearance that, together with hyperglycemia and hyperaminoacidemia, lead to peripheral hyperinsulinemia; systemic hyperinsulinemia may itself contribute to worsen peripheral insulin resistance. Additionally, obesity is accompanied by an impaired incretin effect, causing meal-related glucose intolerance. Lipid-induced impairment of hepatic sensitivity, not only to insulin but potentially also to glucagon, resulting in both hyperinsulinemia and hyperglucagonemia, may therefore contribute to the development of T2D at least in a subset of individuals with NAFLD.

Download Full-text