Lixisenatide resensitizes the insulin‐secretory response to intravenous glucose challenge in people with type 2 diabetes – a study in both people with type 2 diabetes and healthy subjects

ABSTRACT The insulin secretory response in the rat to intravenous glucose was found to be greatly impaired by fasting for three days, whereas that to orally administered glucose was not significantly affected. Rats fasted for two days were given either protein or starch pellets for six hours, and then fasted for a further eighteen hours before the intravenous glucose test. The protein pre-feeding failed to affect significantly the subsequent insulin secretory response to intravenous glucose, whereas starch prefeeding greatly enhanced it. It is suggested that intestinal hormones released by glucose ingestion may exert not only an acute effect on insulin release, but also a 'priming' effect on the insulin release mechanism of the β cell, which enables it to respond to the subsequent stimulus of glucose alone.

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Association of plasma acylcarnitines with insulin sensitivity, insulin secretion, and prediabetes in a biracial cohort

Experimental Biology and Medicine ◽

10.1177/15353702211009493 ◽

2021 ◽

pp. 153537022110094

Author(s):

Ibiye Owei ◽

Nkiru Umekwe ◽

Frankie Stentz ◽

Jim Wan ◽

Sam Dagogo-Jack

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Intravenous Glucose Tolerance Test ◽

Cross Sectional ◽

Parental History ◽

Intravenous Glucose

The ability to predict prediabetes, which affects ∼90 million adults in the US and ∼400 million adults worldwide, would be valuable to public health. Acylcarnitines, fatty acid metabolites, have been associated with type 2 diabetes risk in cross-sectional studies of mostly Caucasian subjects, but prospective studies on their link to prediabetes in diverse populations are lacking. Here, we determined the association of plasma acylcarnitines with incident prediabetes in African Americans and European Americans enrolled in a prospective study. We analyzed 45 acylcarnitines in baseline plasma samples from 70 adults (35 African-American, 35 European-American) with incident prediabetes (progressors) and 70 matched controls (non-progressors) during 5.5-year (mean 2.6 years) follow-up in the Pathobiology of Prediabetes in a Biracial Cohort (POP-ABC) study. Incident prediabetes (impaired fasting glucose/impaired glucose tolerance) was confirmed with OGTT. We measured acylcarnitines using tandem mass spectrometry, insulin sensitivity by hyperinsulinemic euglycemic clamp, and insulin secretion using intravenous glucose tolerance test. The results showed that progressors and non-progressors during POP-ABC study follow-up were concordant for 36 acylcarnitines and discordant for nine others. In logistic regression models, beta-hydroxy butyryl carnitine (C4-OH), 3-hydroxy-isovaleryl carnitine/malonyl carnitine (C5-OH/C3-DC), and octenoyl carnitine (C8:1) were the only significant predictors of incident prediabetes. The combined cut-off plasma levels of <0.03 micromol/L for C4-OH, <0.03 micromol/L for C5-OH/C3-DC, and >0.25 micromol/L for C8:1 acylcarnitines predicted incident prediabetes with 81.9% sensitivity and 65.2% specificity. Thus, circulating levels of one medium-chain and two short-chain acylcarnitines may be sensitive biomarkers for the risk of incident prediabetes among initially normoglycemic individuals with parental history of type 2 diabetes.

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Host–microbiome interactions in human type 2 diabetes following prebiotic fibre (galacto-oligosaccharide) intake

British Journal Of Nutrition ◽

10.1017/s0007114516004086 ◽

2016 ◽

Vol 116 (11) ◽

pp. 1869-1877 ◽

Cited By ~ 35

Author(s):

Camilla Pedersen ◽

Edith Gallagher ◽

Felicity Horton ◽

Richard J. Ellis ◽

Umer Z. Ijaz ◽

...

Keyword(s):

Type 2 Diabetes ◽

Community Structure ◽

Microbial Community ◽

Glucose Tolerance ◽

Microbial Community Structure ◽

Microbial Community Analysis ◽

Intravenous Glucose ◽

Intestinal Microbial Community ◽

Human Type

AbstractAberrant microbiota composition and function have been linked to several pathologies, including type 2 diabetes. In animal models, prebiotics induce favourable changes in the intestinal microbiota, intestinal permeability (IP) and endotoxaemia, which are linked to concurrent improvement in glucose tolerance. This is the first study to investigate the link between IP, glucose tolerance and intestinal bacteria in human type 2 diabetes. In all, twenty-nine men with well-controlled type 2 diabetes were randomised to a prebiotic (galacto-oligosaccharide mixture) or placebo (maltodextrin) supplement (5·5 g/d for 12 weeks). Intestinal microbial community structure, IP, endotoxaemia, inflammatory markers and glucose tolerance were assessed at baseline and post intervention. IP was estimated by the urinary recovery of oral51Cr-EDTA and glucose tolerance by insulin-modified intravenous glucose tolerance test. Intestinal microbial community analysis was performed by high-throughput next-generation sequencing of 16S rRNA amplicons and quantitative PCR. Prebiotic fibre supplementation had no significant effects on clinical outcomes or bacterial abundances compared with placebo; however, changes in the bacterial family Veillonellaceae correlated inversely with changes in glucose response and IL-6 levels (r−0·90,P=0·042 for both) following prebiotic intake. The absence of significant changes to the microbial community structure at a prebiotic dosage/length of supplementation shown to be effective in healthy individuals is an important finding. We propose that concurrent metformin treatment and the high heterogeneity of human type 2 diabetes may have played a significant role. The current study does not provide evidence for the role of prebiotics in the treatment of type 2 diabetes.

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Subcutaneous glucagon-like peptide-1 (7-36) amide is insulinotropic and can cause hypoglycaemia in fasted healthy subjects

Clinical Science ◽

10.1042/cs0950719 ◽

1998 ◽

Vol 95 (6) ◽

pp. 719-724 ◽

Cited By ~ 34

Author(s):

C. Mark B. EDWARDS ◽

Jeannie F. TODD ◽

Mohammad A. GHATEI ◽

Stephen R. BLOOM

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Plasma Glucose ◽

Healthy Subjects ◽

Therapeutic Potential ◽

Double Blind ◽

Gut Hormone ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

1. Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone released postprandially that stimulates insulin secretion, suppresses glucagon secretion and delays gastric emptying. The insulinotropic action of GLP-1 is more potent under hyperglycaemic conditions. Several published studies have indicated the therapeutic potential of subcutaneous GLP-1 in non-insulin-dependent (Type 2) diabetes mellitus. 2. We investigated whether subcutaneous GLP-1, at a dose shown to improve glycaemic control in early Type 2 diabetes, is insulinotropic at normal fasting glucose concentrations. A double-blind, randomized, crossover study of 10 healthy subjects injected with GLP-1 or saline subcutaneously after a 16 h fast was performed. The effect on cardiovascular parameters was also examined. 3. GLP-1 caused a near 5-fold rise in plasma insulin concentration. After treatment with GLP-1, circulating plasma glucose concentrations fell below the normal range in all subjects. One subject had symptoms of hypoglycaemia after GLP-1. A rise in pulse rate was found which correlated with the fall in plasma glucose concentration. An increase in blood pressure occurred with GLP-1 injection which was seen at the same time as the rise in plasma GLP-1 concentrations. 4. This study indicates that subcutaneous GLP-1 can override the normal homoeostatic mechanism maintaining fasting plasma glucose in man, and is also associated with an increase in blood pressure.

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Susceptibility to oxidative stress, insulin resistance, and insulin secretory response in the development of diabetes from obesity

Vojnosanitetski pregled ◽

10.2298/vsp0706391k ◽

2007 ◽

Vol 64 (6) ◽

pp. 391-397 ◽

Cited By ~ 9

Author(s):

Radivoj Kocic ◽

Dusica Pavlovic ◽

Gordana Kocic ◽

Milica Pesic

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

Lipid Peroxidation ◽

Insulin Sensitivity ◽

Healthy Subjects ◽

Critical Role ◽

Secretory Response ◽

Diabetic Patients ◽

Apparent Difference ◽

Insulin Secretory Response

Background/Aim. Oxidative stress plays a critical role in the pathogenesis of various diseases. Recent reports indicate that obesity may induce systemic oxidative stress. The aim of the study was to potentiate oxidative stress as a factor which may aggravate peripheral insulin sensitivity and insulinsecretory response in obesity in this way to potentiate development of diabetes. The aim of the study was also to establish whether insulin-secretory response after glucagonstimulated insulin secretion is susceptible to prooxidant/ antioxidant homeostasis status, as well as to determine the extent of these changes. Methods. A mathematical model of glucose/insulin interactions and C-peptide was used to indicate the degree of insulin resistance and to assess their possible relationship with altered antioxidant/prooxidant homeostasis. The study included 24 obese healthy and 16 obese newly diagnozed non-insulin dependent diabetic patients (NIDDM) as well as 20 control healthy subjects, matched in age. Results. Total plasma antioxidative capacity, erythrocyte and plasma reduced glutathione level were significantly decreased in obese diabetic patients, but also in obese healthy subjects, compared to the values in controls. The plasma lipid peroxidation products and protein carbonyl groups were significantly higher in obese diabetics, more than in obese healthy subjects, compared to the control healthy subjects. The increase of erythrocyte lipid peroxidation at basal state was shown to be more pronounced in obese daibetics, but the apparent difference was obtained in both the obese healthy subjects and obese diabetics, compared to the control values, after exposing of erythrocytes to oxidative stress induced by H2O2. Positive correlation was found between the malondialdehyde (MDA) level and index of insulin sensitivity (FIRI). Conclusion. Increased oxidative stress together with the decreased antioxidative defence seems to contribute to decreased insulin sensitivity and impaired insulin secretory response in obese diabetics, and may be hypothesized to favour the development of diabetes during obesity.

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Fasting serum total bile acid levels are associated with insulin sensitivity, islet β-cell function and glucagon levels in response to glucose challenge in patients with type 2 diabetes

Endocrine Journal ◽

10.1507/endocrj.ej20-0201 ◽

2020 ◽

Vol 67 (11) ◽

pp. 1107-1117

Author(s):

Xiao-hua Wang ◽

Feng Xu ◽

Ming Cheng ◽

Xing Wang ◽

Dong-mei Zhang ◽

...

Keyword(s):

Type 2 Diabetes ◽

Bile Acid ◽

Insulin Sensitivity ◽

Cell Function ◽

Total Bile Acid ◽

Fasting Serum ◽

Glucose Challenge

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Branched-Chain Amino Acid Metabolism is Regulated by ERRα and is Further Impaired by Glucose Loading in Type 2 Diabetes

10.1101/2020.07.24.218099 ◽

2020 ◽

Author(s):

Rasmus J.O. Sjögren ◽

David Rizo-Roca ◽

Alexander V. Chibalin ◽

Elin Chorell ◽

Regula Furrer ◽

...

Keyword(s):

Type 2 Diabetes ◽

Plasma Metabolites ◽

Peripheral Tissues ◽

Branched Chain Amino Acid ◽

Glucose Challenge ◽

Metabolic Inflexibility ◽

Branched Chain ◽

Estrogen Related Receptor ◽

Dependent Mechanism

SUMMARYIncreased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes (T2D) pathogenesis. However, most metabolomic studies in T2D are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a glucose challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism in T2D is partially unknown. Using metabolomic and gene expression approaches, we found that impairments in BCAA catabolism in T2D patients under fasting conditions are exacerbated after a glucose load, concomitant with downregulated expression of BCAA-related genes in skeletal muscle. We identified a key regulatory role for Estrogen-Related Receptor α (ERRα) in PGC-1α-mediated upregulation of BCAA genes and leucine oxidation. Thus, metabolic inflexibility in T2D impacts BCAA homeostasis and the transcriptional regulation of BCAA genes via a PGC-1α/ERRα-dependent mechanism.

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Evaluation of the effect of MTNR1B rs10830963 gene polymorphism on the therapeutic efficacy of nateglinide in treating type 2 diabetes among Chinese Han patients

10.21203/rs.2.14474/v1 ◽

2019 ◽

Author(s):

Jinfang Song ◽

Mingzhu Zhang ◽

Jiang Ni ◽

Tao Wang ◽

Yi-Qing Zhao

Keyword(s):

Type 2 Diabetes ◽

Gene Polymorphism ◽

Therapeutic Efficacy ◽

Healthy Subjects ◽

Venous Blood ◽

Melting Curve ◽

Allelic Frequency ◽

Model Assessment ◽

Chinese Han

Abstract Background: Several studies have shown the association of polymorphisms in the MTNR1B gene with type 2 diabetes mellitus (T2DM). However, there is no evidence about the impacts of its genetic polymorphism on the therapeutic efficacy of nateglinide. Therefore, this prospective case-control study was designed to investigate the effect of MTNR1B rs10830963 gene polymorphism on the therapeutic efficacy of nateglinide in treating T2DM. Methods: We genotyped 200 healthy subjects using the method of the high resolution of melting curve (HRM). A total of 60 T2DM patients were enrolled and given nateglinide (360 mg/d) for 8 weeks orally who had the same genotypes CYP2C9*1 and SLCO1B1 521TT respectively. The outcome was measured by collecting the venous blood samples before and at the 8th week of the treatment. Also, anthropometric measurements, glucose, and lipid metabolism were determined before and after the nateglinide treatment. Results: It was found that the risk G allelic frequency of MTNR1B rs10830963 was higher in T2DM patients when compared with the healthy subjects (P<0.05). 60 newly diagnosed patients with type 2 diabetes after completing the eight weeks treatment came for the follow-up visit and showed a reduction in fasting plasma glucose (FPG) levels with an increase in homeostasis model assessment for β cell HOMA-β in the carriers of genotype CG + GG at rs10830963, when compared with the wild-type CC (P <0.05). Conclusion: Thus, it was found that the MTNR1B rs10830963 polymorphism was associated with the therapeutic efficacy of nateglinide in T2DM patients. Also, the CC homozygotes had a better effect than G allele carriers. Trial registration: This study was registered in the Chinese Clinical Trial Register (No. ChiCTR-CCC13003536).

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