Identification of Multiple Pancreatic and Extra-Pancreatic Pathways Underlying the Glucose-Lowering Actions of Acacia arabica Bark in Type-2 Diabetes and Isolation of Active Phytoconstituents

Acacia arabica is used traditionally to treat a variety of ailments, including diabetes. This study elucidated the antidiabetic actions of A. arabica bark together with the isolation of bioactive molecules. Insulin secretion and signal transduction were measured using clonal β cells and mouse islets. Glucose uptake was assessed using 3T3-L1 adipocytes, and in vitro systems assessed additional glucose-lowering actions. High-fat-fed (HFF) obese rats were used for in vivo evaluation, and phytoconstituents were isolated and characterised by RP-HPLC followed by LC-MS and NMR. Hot-water extract of A. arabica (HWAA) increased insulin release from clonal β cells and mouse islets by 1.3–6.8-fold and 1.6–3.2-fold, respectively. Diazoxide, verapamil and calcium-free conditions decreased insulin-secretory activity by 30–42%. In contrast, isobutylmethylxanthine (IBMX), tolbutamide and 30 mM KCl potentiated the insulin-secretory effects. The mechanism of actions of HWAA involved membrane depolarisation and elevation of intracellular Ca2+ together with an increase in glucose uptake by 3T3-L1 adipocytes, inhibition of starch digestion, glucose diffusion, dipeptidyl peptidase-IV (DPP-IV) enzyme activity and protein glycation. Acute HWAA administration (250 mg/5 mL/kg) enhanced glucose tolerance and plasma insulin in HFF obese rats. Administration of HWAA (250 mg/5 mL/kg) for 9 days improved glucose homeostasis and β-cell functions, thereby improving glycaemic control, and circulating insulin. Isolated phytoconstituents, including quercetin and kaempferol, increased insulin secretion in vitro and improved glucose tolerance. The results indicate that HWAA has the potential to treat type 2 diabetes as a dietary supplement or as a source of antidiabetic agents, including quercetin and kaempferol.

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Teucrium polium: Potential Drug Source for Type 2 Diabetes Mellitus

Biology ◽

10.3390/biology11010128 ◽

2022 ◽

Vol 11 (1) ◽

pp. 128

Author(s):

Yaser Albadr ◽

Andrew Crowe ◽

Rima Caccetta

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Insulin Secretion ◽

Β Cells ◽

Pancreatic Β Cells ◽

Glucose Levels ◽

Teucrium Polium

The prevalence of type 2 diabetes mellitus is rising globally and this disease is proposed to be the next pandemic after COVID-19. Although the cause of type 2 diabetes mellitus is unknown, it is believed to involve a complex array of genetic defects that affect metabolic pathways which eventually lead to hyperglycaemia. This hyperglycaemia arises from an inability of the insulin-sensitive cells to sufficiently respond to the secreted insulin, which eventually results in the inadequate secretion of insulin from pancreatic β-cells. Several treatments, utilising a variety of mechanisms, are available for type 2 diabetes mellitus. However, more medications are needed to assist with the optimal management of the different stages of the disease in patients of varying ages with the diverse combinations of other medications co-administered. Throughout modern history, some lead constituents from ancient medicinal plants have been investigated extensively and helped in developing synthetic antidiabetic drugs, such as metformin. Teucrium polium L. (Tp) is a herb that has a folk reputation for its antidiabetic potential. Previous studies indicate that Tp extracts significantly decrease blood glucose levels r and induce insulin secretion from pancreatic β-cells in vitro. Nonetheless, the constituent/s responsible for this action have not yet been elucidated. The effects appear to be, at least in part, attributable to the presence of selected flavonoids (apigenin, quercetin, and rutin). This review aims to examine the reported glucose-lowering effect of the herb, with a keen focus on insulin secretion, specifically related to type 2 diabetes mellitus. An analysis of the contribution of the key constituent flavonoids of Tp extracts will also be discussed.

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Exendin-4 Improves β-Cell Function in Autophagy-Deficient β-Cells

Endocrinology ◽

10.1210/en.2013-1578 ◽

2013 ◽

Vol 154 (12) ◽

pp. 4512-4524 ◽

Cited By ~ 35

Author(s):

Hiroko Abe ◽

Toyoyoshi Uchida ◽

Akemi Hara ◽

Hiroki Mizukami ◽

Koji Komiya ◽

...

Keyword(s):

Type 2 Diabetes ◽

Cell Death ◽

Insulin Secretion ◽

Glucose Tolerance ◽

Cell Function ◽

Apoptotic Cell ◽

Β Cells ◽

Β Cell ◽

Β Cell Function

Autophagy is cellular machinery for maintenance of β-cell function and mass. The implication of autophagy failure in β-cells on the pathophysiology of type 2 diabetes and its relation to the effect of treatment of diabetes remains elusive. Here, we found increased expression of p62 in islets of db/db mice and patients with type 2 diabetes mellitus. Treatment with exendin-4, a glucagon like peptide-1 receptor agonist, improved glucose tolerance in db/db mice without significant changes in p62 expression in β-cells. Also in β-cell-specific Atg7-deficient mice, exendin-4 efficiently improved blood glucose level and glucose tolerance mainly by enhanced insulin secretion. In addition, we found that exendin-4 reduced apoptotic cell death and increased proliferating cells in the Atg7-deficient islets, and that exendin-4 counteracted thapsigargin-induced cell death of isolated islets augmented by autophagy deficiency. Our results suggest the potential involvement of reduced autophagy in β-cell dysfunction in type 2 diabetes. Without altering the autophagic state in β-cells, exendin-4 improves glucose tolerance associated with autophagy deficiency in β-cells. This is mainly achieved through augmentation of insulin secretion. In addition, exendin-4 prevents apoptosis and increases the proliferation of β-cells associated with autophagy deficiency, also without altering the autophagic machinery in β-cells.

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1782-P: Impact of Treatment with Medication vs. Laparoscopic Gastric Banding (GB) on ß-Cell Function in Adults with Impaired Glucose Tolerance (IGT) or Type 2 Diabetes (T2D) in the Restoring Insulin Secretion (RISE) Study

Diabetes ◽

10.2337/db20-1782-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 1782-P

Author(s):

DAVID A. EHRMANN ◽

SHARON EDELSTEIN ◽

ANNY XIANG ◽

THOMAS A. BUCHANAN ◽

SILVA A. ARSLANIAN ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Glucose Tolerance ◽

Gastric Banding ◽

Impaired Glucose Tolerance ◽

Cell Function ◽

Laparoscopic Gastric Banding

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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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Postprandial glucose-lowering effect of premeal consumption of protein-enriched, dietary fiber-fortified bar in individuals with type 2 diabetes mellitus or normal glucose tolerance

Journal of Diabetes Investigation ◽

10.1111/jdi.12831 ◽

2018 ◽

Vol 9 (5) ◽

pp. 1110-1118 ◽

Cited By ~ 10

Author(s):

Jae Hyun Bae ◽

Lee Kyung Kim ◽

Se Hee Min ◽

Chang Ho Ahn ◽

Young Min Cho

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Glucose Tolerance ◽

Postprandial Glucose ◽

Normal Glucose Tolerance ◽

Glucose Lowering ◽

Normal Glucose ◽

Glucose Lowering Effect

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RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes

10.1101/2021.12.16.466282 ◽

2021 ◽

Author(s):

John T Walker ◽

Diane C Saunders ◽

Vivek Rai ◽

Chunhua Dai ◽

Peter Orchard ◽

...

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Association Studies ◽

Critical Role ◽

Regulatory Elements ◽

Genome Wide Association Studies ◽

Β Cells ◽

Β Cell ◽

Gene Regulatory

A hallmark of type 2 diabetes (T2D), a major cause of world-wide morbidity and mortality, is dysfunction of insulin-producing pancreatic islet β cells. T2D genome-wide association studies (GWAS) have identified hundreds of signals, mostly in the non-coding genome and overlapping β cell regulatory elements, but translating these into biological mechanisms has been challenging. To identify early disease-driving events, we performed single cell spatial proteomics, sorted cell transcriptomics, and assessed islet physiology on pancreatic tissue from short-duration T2D and control donors. Here, through integrative analyses of these diverse modalities, we show that multiple gene regulatory modules are associated with early-stage T2D β cell-intrinsic defects. One notable example is the transcription factor RFX6, which we show is a highly connected β cell hub gene that is reduced in T2D and governs a gene regulatory network associated with insulin secretion defects and T2D GWAS variants. We validated the critical role of RFX6 in β cells through direct perturbation in primary human islets followed by physiological and single nucleus multiome profiling, which showed reduced dynamic insulin secretion and large-scale changes in the β cell transcriptome and chromatin accessibility landscape. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs, and individuals and thus we anticipate this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits with GWAS data.

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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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