The Expression of Aldolase B in Islets Is Negatively Associated With Insulin Secretion in Humans

Abstract Context Reduced β-cell mass, impaired islet function, and dedifferentiation are considered causal to development of hyperglycemia and type 2 diabetes. In human cohort studies, changes of islet cell–specific expression patterns have been associated with diabetes but not directly with in vivo insulin secretion. Objective This study investigates alterations of islet gene expression and corresponding gene variants in the context of in vivo glycemic traits from the same patients. Methods Fasting blood was collected before surgery, and pancreatic tissue was frozen after resection from 18 patients undergoing pancreatectomy. Islet tissue was isolated by laser capture microdissection. Islet transcriptome was analyzed using microarray and quantitative RT-PCR. Proteins were examined by immunohistochemistry and western blotting. The association of gene variants with insulin secretion was investigated with oral glucose tolerance test (OGTT)-derived insulin secretion measured in a large cohort of subjects at increased risk of type 2 diabetes and with hyperglycemic clamp in a subset. Results Differential gene expression between islets from normoglycemic and hyperglycemic patients was prominent for the glycolytic enzyme ALDOB and the obesity-associated gene FAIM2. The mRNA levels of both genes correlated negatively with insulin secretion and positively with HbA1c. Islets of hyperglycemic patients displayed increased ALDOB immunoreactivity in insulin-positive cells, whereas α- and δ-cells were negative. Exposure of isolated islets to hyperglycemia augmented ALDOB expression. The minor allele of the ALDOB variant rs550915 associated with significantly higher levels of C-peptide and insulin during OGTT and hyperglycemic clamp, respectively. Conclusion Our analyses suggest that increased ALDOB expression in human islets is associated with lower insulin secretion.

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Microbiota-related metabolites and the risk of type 2 diabetes

10.2337/dc20-1234/suppl.12009102 ◽

2020 ◽

Author(s):

Jagadish Vangipurapu ◽

Lilian Fernandes Silva ◽

Teemu Kuulasmaa ◽

Ulf Smith ◽

Markku Laakso

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Oral Glucose ◽

Microbial Metabolites ◽

Cross Sectional ◽

Metabolomics Data ◽

Incident Type ◽

Increased Risk

OBJECTIVE: Recent studies have highlighted the significance of microbiome in human health and disease. Changes in the metabolites produced by microbiota have been implicated in several diseases. Our objective was to identify microbiome metabolites that are associated with type 2 diabetes. RESEARCH DESIGN AND METHODS: 5,181 participants from the cross-sectional METabolic Syndrome In Men (METSIM) study that included Finnish men (age 57 ± 7 years, body mass index 26.5 ± 3.5 kg/m2) having metabolomics data available were included in our study. Metabolomics analysis was performed based on fasting plasma samples. Based on an oral glucose tolerance test, Matsuda ISI and Disposition index were calculated as markers of insulin sensitivity and insulin secretion. A total of 4,851 participants had a 7.4-year follow-up visit and 522 participants developed type 2 diabetes. RESULTS: Creatine, 1-palmitoleoylglycerol(16:1), urate, 2-hydroxybutyrate/2-hydroxyisobutyrate, xanthine, xanthurenate, kynurenate, 3-(4-hydroxyphenyl)lactate, 1-oleoylglycerol(18:1), 1-myristoylglycerol(14:0), dimethylglycine and 2-hydroxyhippurate(salicylurate) were significantly associated with an increased risk of type 2 diabetes. These metabolites were associated with decreased insulin secretion or insulin sensitivity or both. Among the metabolites that were associated with a decreased risk of type 2 diabetes, 1-linoleoyl-glycerophosphocholine (18:2) significantly reduced the risk of type 2 diabetes. CONCLUSIONS: Several novel and previously reported microbial metabolites related to gut microbiota were associated with an increased risk of incident type 2 diabetes, and they were also associated with decreased insulin secretion and insulin sensitivity. Microbial metabolites are important biomarkers for the risk of type 2 diabetes.

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Microbiota-related metabolites and the risk of type 2 diabetes

10.2337/dc20-1234/suppl.12009102.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jagadish Vangipurapu ◽

Lilian Fernandes Silva ◽

Teemu Kuulasmaa ◽

Ulf Smith ◽

Markku Laakso

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Insulin Sensitivity ◽

Oral Glucose ◽

Microbial Metabolites ◽

Cross Sectional ◽

Metabolomics Data ◽

Incident Type ◽

Increased Risk

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Habitual late sleep initiation is associated with increased incidence of type 2 diabetes mellitus in Korean adults: the Korean Genome and Epidemiology Study

SLEEP ◽

10.1093/sleep/zsz090 ◽

2019 ◽

Vol 42 (7) ◽

Cited By ~ 1

Author(s):

Ji A Seo ◽

Da Young Lee ◽

Ji Hee Yu ◽

Hyunjoo Cho ◽

Seung Ku Lee ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Sleep Duration ◽

Significant Risk ◽

Oral Glucose ◽

Initiation Time ◽

Epidemiology Study ◽

Increased Risk ◽

The Impact

Abstract Study Objectives Although sleep duration and quality were significant risk factors of type 2 diabetes (T2D), the impact of sleep initiation time on the development of T2D has not been studied in large longitudinal studies. Methods A total of 3689 participants without diabetes aged 40–69 years at baseline were enrolled from the Korean Genome and Epidemiology Study and followed up for 12 years. Participants were categorized based on habitual sleep initiation time by questionnaire as follows: 20:00–22:59 (early sleepers, ES, n = 766), 23:00–00:59 (usual sleepers, US, n = 2407), and 1:00–5:59 (late sleepers, LS, n = 516). Incident T2D was identified biennially by fasting plasma glucose or 2-hour glucose after 75-g oral glucose loading or use of anti-diabetes medication. Results During follow-up, 820 cases of T2D were documented and the LS group showed the highest increase in insulin resistance. Hazard ratio (HR) (95% confidence interval) for T2D of LS compared to ES was 1.34 (1.04–1.74) after adjustment for covariates including sleep duration. The impact of late sleep on the development of T2D was more evident in older individuals (≥65 years at baseline) (HR = 4.24 [1.42–12.68] in older LS vs. older ES, HR = 1.27 [1.00–1.62] in younger LS vs. younger ES, pinteraction = 0.002). In addition, LS with low insulin secretion and sensitivity showed an approximately fivefold increased risk for T2D compared to ES with high insulin secretion and sensitivity. Conclusions/Interpretation Habitual late sleep initiation is a significant risk factor for T2D in Koreans, especially in people with lower insulin sensitivity, lower β-cell function, and older age.

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Effects on insulin secretion and insulin action of a 48-h reduction of plasma free fatty acids with acipimox in nondiabetic subjects genetically predisposed to type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00624.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. E1775-E1781 ◽

Cited By ~ 59

Author(s):

Kenneth Cusi ◽

Sangeeta Kashyap ◽

Amalia Gastaldelli ◽

Mandeep Bajaj ◽

Eugenio Cersosimo

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Family History ◽

Second Phase ◽

Β Cell ◽

C Peptide ◽

Hyperglycemic Clamp ◽

History Of ◽

Plasma Ffa

Elevated plasma FFA cause β-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not in nondiabetic subjects without a family history of T2DM. To determine whether lowering plasma FFA with acipimox, an antilipolytic nicotinic acid derivative, may enhance insulin secretion, nine FH+ volunteers were admitted twice and received in random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations were measured from 0800 to 2400. On day 3, insulin secretion rates (ISRs) were assessed during a +125 mg/dl hyperglycemic clamp. Acipimox reduced 48-h plasma FFA by 36% ( P < 0.001) and increased the plasma C-peptide relative to the plasma glucose concentration or ΔC-peptide/Δglucose AUC (+177%, P = 0.02), an index of improved β-cell function. Acipimox improved insulin sensitivity (M/I) 26.1 ± 5% ( P < 0.04). First- (+19 ± 6%, P = 0.1) and second-phase (+31 ± 6%, P = 0.05) ISRs during the hyperglycemic clamp also improved. This was particularly evident when examined relative to the prevailing insulin resistance [1/(M/I)], as both first- and second-phase ISR markedly increased by 29 ± 7 ( P < 0.05) and 41 ± 8% ( P = 0.02). There was an inverse correlation between fasting FFA and first-phase ISR ( r2 = 0.31, P < 0.02) and acute (2–4 min) glucose-induced insulin release after acipimox ( r2 =0.52, P < 0.04). In this proof-of-concept study in FH+ individuals predisposed to T2DM, a 48-h reduction of plasma FFA improves day-long meal and glucose-stimulated insulin secretion. These results provide additional evidence for the important role that plasma FFA play regarding insulin secretion in FH+ subjects predisposed to T2DM.

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Interplay of Dinner Timing and MTNR1B Type 2 Diabetes Risk Variant on Glucose Tolerance and Insulin Secretion: A Randomized Crossover Trial

10.2337/figshare.17122142 ◽

2022 ◽

Author(s):

Marta Garaulet ◽

Jesus Lopez-Minguez ◽

Hassan S Dashti ◽

Céline Vetter ◽

Antonio Miguel Hernández-Martínez ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Glucose Tolerance ◽

Area Under The Curve ◽

Serum Levels ◽

Postprandial Glucose ◽

Oral Glucose ◽

Elevated Concentration ◽

Endogenous Melatonin

Objective: We tested whether the concurrence of food intake and elevated concentration of endogenous melatonin, as occurs in late eating, results in impaired glucose control, in particular in carriers of the type 2 diabetes-associated G allele in the melatonin-receptor-1-b gene (MTNR1B). Research Design and Methods: In a Spanish natural late eating population, a randomized, cross-over study design was performed, following an 8-h fast. Each participant (n=845) underwent two evening 2-h 75g oral glucose tolerance tests (OGTT): an early condition scheduled 4 hours prior to habitual bedtime (“early dinner-timing”), and a late condition scheduled 1 hour prior to habitual bedtime (“late dinner-timing”), simulating an early and a late dinner timing, respectively. Differences in postprandial glucose and insulin responses were determined using incremental area under the curve (AUC) calculated by the trapezoidal method between early and late dinner-timing. Results: Melatonin serum levels were 3.5-fold higher in the late vs. early condition, with late dinner-timing resulting in 6.7% lower insulin area-under-the-curve (AUC) and 8.3% higher glucose AUC. In the late condition MTNR1B G-allele carriers had lower glucose tolerance than non-carriers. Genotype differences in glucose tolerance were attributed to reductions in β-cell function (Pint AUCgluc=0.009, Pint CIR=0.022, Pint DI=0.018). Conclusions: Concurrently high endogenous melatonin and carbohydrate intake, as typical for late eating, impair glucose tolerance, especially in MTNR1B G-risk-allele carriers, attributable to insulin secretion defects.

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Genetic effect of Type 2 diabetes to the progression of neurological diseases

10.7287/peerj.preprints.27323 ◽

2018 ◽

Author(s):

Md Habibur Rahman ◽

Silong Peng ◽

Chen Chen ◽

Pietro Lio’ ◽

Mohammad Ali Moni

Keyword(s):

Gene Expression ◽

Type 2 Diabetes ◽

Drug Targets ◽

Neurological Diseases ◽

Genetic Effect ◽

Neurological Dysfunction ◽

Transcriptional Analysis ◽

Increased Risk ◽

Benchmark Datasets

Neurological diseases (NDs) are progressive disorder often advances with age and comorbidities of Type 2 diabetes (T2D). Epidemiological, clinical and neuropathological evidence advocate that patients with T2D are at an increased risk of getting NDs. However, it is very little known how T2D affects the risk and severity of NDs. To tackle these problems, we employed a transcriptional analysis of affected tissues using agnostic approaches to identify overlapping cellular functions. In this study, we examined gene expression microarray human datasets along with control and disease-affected individuals. Differentially expressed genes (DEG) were identified for both T2D and NDs that includes Alzheimer Disease (AD), Parkinson Disease (PD), Amyotrophic Lateral Sclerosis (ALS), Epilepsy Disease (ED), Huntington Disease (HD), Cerebral Palsy (CP) and Multiple Sclerosis Disease (MSD). We have developed genetic association and diseasome network of T2D and NDs based on the neighborhood-based benchmarking and multilayer network topology approaches. Overlapping DEG sets go through protein-protein interaction and gene enrichment using pathway analysis and gene ontology methods, identifying numerous candidate common genes and pathways. Gene expression analysis platforms have been extensively used to investigate altered pathways and to identify potential biomarkers and drug targets. Finally, we validated our identified biomarkers using the gold benchmark datasets which identified corresponding relations of T2D and NDs. Therapeutic targets aimed at attenuating identified altered pathway could ameliorate neurological dysfunction in a T2D patient.

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Abstract 424: An IFNg-regulated Macrophage Protein Network Links Type 2 Diabetes to Atherosclerosis

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.424 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Catherine A Reardon ◽

Amulya Lingaraju ◽

Kelly Q Schoenfelt ◽

Guolin Zhou ◽

Ning-Chun Liu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Foam Cell ◽

Cell Formation ◽

Foam Cell Formation ◽

Increased Risk ◽

Macrophage Dysfunction ◽

Macrophage Protein

Type 2 diabetics have a higher risk for atherosclerosis, but the mechanisms underlying the increased risk are poorly understood. Macrophages, which are activated in type 2 diabetes (T2D) and have a role in all stages of atherogenesis, are an attractive link. Our hypothesis is that T2D promotes macrophage dysfunction to promote atherosclerosis. To investigate the relationship between T2D and macrophage dysfunction, we used a proteomics approach to identify dysregulated proteins secreted from peritoneal macrophages in a diet induced mouse model of obesity and insulin resistance in the absence of hypercholesterolemia. Twenty-seven T2D responsive proteins were identified that predict defects in many of the critical functions of macrophages in atherosclerosis (e.g. decreased apoE- cholesterol efflux; decreased MFGE8 – efferocytosis, increased MMP12- matrix degradation). The macrophages from lean and obese mice were not lipid loaded, but the obese macrophages accumulated significantly more cholesterol when exposed to high levels of atherogenic lipoproteins in vitro suggesting that dysregulation of the T2D responsive proteins in diabetic mice render macrophages more susceptible to cholesterol loading. Importantly, many of these same protein changes, which were present in atherosclerotic Ldlr-/- mice with T2D, were normalized when these mice were fed non-diabetogenic hypercholesterolemic diets. Thus, foam cell formation in the presence and absence of T2D produces distinct effects on macrophage protein levels, and hence function. Further, we identify IFNγ as a mediator of the T2D responsive protein dysfunction. IFNγ, but not other cytokines, insulin or glucose, promote the T2D responsive protein dysregulation and increased susceptibility to cholesterol accumulation in vitro and the dysregulation is not observed in macrophage foam cells obtained from obese, diabetic IFNγ receptor 1 knockout animals. We also demonstrate that IFNγ can target these proteins in arterial wall macrophages in vivo . These studies suggest that IFNγ is an important mediator of macrophage dysfunction in T2D that may contribute to the enhanced cardiovascular risk in these patients.

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Insulin secretion-independent effects of GLP-1 on canine liver glucose metabolism do not involve portal vein GLP-1 receptors

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00121.2005 ◽

2005 ◽

Vol 289 (5) ◽

pp. G806-G814 ◽

Cited By ~ 37

Author(s):

Dominique Dardevet ◽

Mary Courtney Moore ◽

Catherine A. DiCostanzo ◽

Ben Farmer ◽

Doss W. Neal ◽

...

Keyword(s):

Insulin Secretion ◽

Portal Vein ◽

Glucose Disposal ◽

Control Group ◽

Oral Glucose ◽

Oral Glucose Tolerance Testing ◽

Hyperglycemic Clamp ◽

Independent Effects ◽

Hepatic Portal

Whether glucagon-like peptide (GLP)-1 requires the hepatic portal vein to elicit its insulin secretion-independent effects on glucose disposal in vivo was assessed in conscious dogs using tracer and arteriovenous difference techniques. In study 1, six conscious overnight-fasted dogs underwent oral glucose tolerance testing (OGTT) to determine target GLP-1 concentrations during clamp studies. Peak arterial and portal values during OGTT ranged from 23 to 65 pM and from 46 to 113 pM, respectively. In study 2, we conducted hyperinsulinemic-hyperglycemic clamp experiments consisting of three periods (P1, P2, and P3) during which somatostatin, glucagon, insulin and glucose were infused. The control group received saline, the PePe group received GLP-1 (1 pmol·kg−1·min−1) peripherally, the PePo group received GLP-1 (1 pmol·kg−1·min−1) peripherally (P2) and then intraportally (P3), and the PeHa group received GLP-1 (1 pmol·kg−1·min−1) peripherally (P2) and then through the hepatic artery (P3) to increase the hepatic GLP-1 load to the same extent as in P3 in the PePo group ( n = 8 dogs/group). Arterial GLP-1 levels increased similarly in all groups during P2 (∼50 pM), whereas portal GLP-1 levels were significantly increased (2-fold) in the PePo vs. PePe and PeHa groups during P3. During P2, net hepatic glucose uptake (NHGU) increased slightly but not significantly (vs. P1) in all groups. During P3, GLP-1 increased NHGU in the PePo and PeHa groups more than in the control and PePe groups (change of 10.8 ± 1.3 and 10.6 ± 1.0 vs. 5.7 ± 1.0 and 5.4 ± 0.8 μmol·kg−1·min−1, respectively, P < 0.05). In conclusion, physiological GLP-1 levels increase glucose disposal in the liver, and this effect does not involve GLP-1 receptors located in the portal vein.

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The Wnt signaling pathway effector TCF7L2 is upregulated by insulin and represses hepatic gluconeogenesis

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00249.2012 ◽

2012 ◽

Vol 303 (9) ◽

pp. E1166-E1176 ◽

Cited By ~ 44

Author(s):

Wilfred Ip ◽

Weijuan Shao ◽

Yu-ting Alex Chiang ◽

Tianru Jin

Keyword(s):

Gene Expression ◽

Type 2 Diabetes ◽

Transcription Factor ◽

Wnt Signaling ◽

Wnt Signaling Pathway ◽

Glucose Production ◽

Hepatic Gluconeogenesis

Certain single nucleotide polymorphisms (SNPs) in transcription factor 7-like 2 (TCF7L2) are strongly associated with the risk of type 2 diabetes. TCF7L2 and β-catenin (β-cat) form the bipartite transcription factor cat/TCF in stimulating Wnt target gene expression. cat/TCF may also mediate the effect of other signaling cascades, including that of cAMP and insulin in cell-type specific manners. As carriers of TCF7L2 type 2 diabetes risk SNPs demonstrated increased hepatic glucose production, we aimed to determine whether TCF7L2 expression is regulated by nutrient availability and whether TCF7L2 and Wnt regulate hepatic gluconeogenesis. We examined hepatic Wnt activity in the TOPGAL transgenic mouse, assessed hepatic TCF7L2 expression in mice upon feeding, determined the effect of insulin on TCF7L2 expression and β-cat Ser675 phosphorylation, and investigated the effect of Wnt activation and TCF7L2 knockdown on gluconeogenic gene expression and glucose production in hepatocytes. Wnt activity was observed in pericentral hepatocytes in the TOPGAL mouse, whereas TCF7L2 expression was detected in human and mouse hepatocytes. Insulin and feeding stimulated hepatic TCF7L2 expression in vitro and in vivo, respectively. In addition, insulin activated β-cat Ser675 phosphorylation. Wnt activation by intraperitoneal lithium injection repressed hepatic gluconeogenic gene expression in vivo, whereas lithium or Wnt-3a reduced gluconeogenic gene expression and glucose production in hepatic cells in vitro. Small interfering RNA-mediated TCF7L2 knockdown increased glucose production and gluconeogenic gene expression in cultured hepatocytes. These observations suggest that Wnt signaling and TCF7L2 are negative regulators of hepatic gluconeogenesis, and TCF7L2 is among the downstream effectors of insulin in hepatocytes.

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In Vivo Efficacy of HD0471953: A Novel GPR119 Agonist for the Treatment of Type 2 Diabetes Mellitus

Journal of Diabetes Research ◽

10.1155/2013/269569 ◽

2013 ◽

Vol 2013 ◽

pp. 1-6 ◽

Cited By ~ 12

Author(s):

So Ra Kim ◽

Dae-Hoon Kim ◽

Soo Hyun Park ◽

Young Seok Kim ◽

Chun Hwa Kim ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Tolerance Test ◽

Oral Glucose ◽

Dependent Manner ◽

Gpr119 Agonist ◽

Dose Dependent

G-protein coupled receptor 119 (GPR119) has emerged as a promising new target for the treatment of type 2 diabetes mellitus. The expression of GPR119 on the pancreatic B cells and intestinal L cells provides a unique opportunity for a single drug to promote insulin and GLP-1 secretion. In this study, we identified a novel small molecule GPR119 agonist, HD0471953, from our large library of synthetic compounds based on its ability to anti-hyperglycemic effects on T2DM murine models. We have tested the acute efficacy of HD0471953 by the oral glucose tolerance test (OGTT) with normal C57BL/6J mice. Then, chronic administrations of HD0471953 were performed to evaluate the efficacy on various diabetic rodent models. Single administration of HD0471953 showed improved glycemic control with a dose-dependent manner in OGTT with normal mice, and the insulin and GLP-1 were also increased. To identify chronic efficacy, we have observed a decline of blood glucose and fasting insulin in a dose-dependent manner of 10, 20, and 50 mpk indb/dbmice. The results suggest that HD0471953 may be a potentially promising anti-hyperglycemic agent for the treatment of patients with type 2 diabetes mellitus.

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