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Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity.
Rutter, GA, Georgiadou, E, Martinez-Sanchez, A, Pullen, TJ
Diabetologia. 2020;(10):1990-1998
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Abstract
All forms of diabetes mellitus involve the loss or dysfunction of pancreatic beta cells, with the former predominating in type 1 diabetes and the latter in type 2 diabetes. Deeper understanding of the coupling mechanisms that link glucose metabolism in these cells to the control of insulin secretion is therefore likely to be essential to develop new therapies. Beta cells display a remarkable metabolic specialisation, expressing high levels of metabolic sensing enzymes, including the glucose transporter GLUT2 (encoded by SLC2A2) and glucokinase (encoded by GCK). Genetic evidence flowing from both monogenic forms of diabetes and genome-wide association studies for the more common type 2 diabetes, supports the importance for normal glucose-stimulated insulin secretion of metabolic signalling via altered ATP generation, while also highlighting unsuspected roles for Zn2+ storage, intracellular lipid transfer and other processes. Intriguingly, genes involved in non-oxidative metabolic fates of the sugar, such as those for lactate dehydrogenase (LDHA) and monocarboxylate transporter-1 ([MCT-1] SLC16A1), as well as the acyl-CoA thioesterase (ACOT7) and others, are selectively repressed ('disallowed') in beta cells. Furthermore, mutations in genes critical for mitochondrial oxidative metabolism, such as TRL-CAG1-7 encoding tRNALeu, are linked to maternally inherited forms of diabetes. Correspondingly, impaired Ca2+ uptake into mitochondria, or collapse of a normally interconnected mitochondrial network, are associated with defective insulin secretion. Here, we suggest that altered mitochondrial metabolism may also impair beta cell-beta cell communication. Thus, we argue that defective oxidative glucose metabolism is central to beta cell failure in diabetes, acting both at the level of single beta cells and potentially across the whole islet to impair insulin secretion. Graphical abstract.
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Multiple risk factors for diabetes mellitus in patients with chronic pancreatitis: A multicentre study of 1117 cases.
Olesen, SS, Poulsen, JL, Novovic, S, Nøjgaard, C, Kalaitzakis, E, Jensen, NM, Engjom, T, Tjora, E, Waage, A, Hauge, T, et al
United European gastroenterology journal. 2020;(4):453-461
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Abstract
BACKGROUND Diabetes mellitus is a common complication of chronic pancreatitis. It is traditionally considered to develop as a consequence of beta cell loss, but there might be additional factors. Recent studies have highlighted the importance of type 2 diabetes-related risk factors in this context and population-based studies show increased risk of diabetes following acute pancreatitis. The aim of this study was to explore multiple risk factors for diabetes in patients with chronic pancreatitis. METHODS We conducted a multicentre, cross-sectional study of patients with definitive chronic pancreatitis according to the M-ANNHEIM criteria. We used multivariable logistic regression models to determine risk factors independently associated with diabetes. RESULTS The study included 1117 patients of whom 457 (40.9 %) had diabetes. The mean age was 52.8 ± 14.2 years and 67% were men. On multivariate analysis, parameters indicative of beta cell loss (pancreatic calcification, exocrine insufficiency, pancreatic resection) were confirmed as independent risk factors for diabetes (all p ≤ 0.02). In addition, type 2 diabetes-related risk factors (dyslipidaemia and overweight/obesity) were associated with the presence of diabetes (all p ≤ 0.002). Patients with a history of pancreatic fluid collections (indicative of previous attacks of acute pancreatitis) had a marginally increased risk of diabetes (p = 0.07). CONCLUSION In patients with chronic pancreatitis the presence of diabetes is associated with multiple risk factors including type 2 diabetes-related factors. Our observations attest to the understanding of this entity and may have implications for treatment.
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Early beta cell dysfunction vs insulin hypersecretion as the primary event in the pathogenesis of dysglycaemia.
Esser, N, Utzschneider, KM, Kahn, SE
Diabetologia. 2020;(10):2007-2021
Abstract
Obesity and insulin resistance are associated with the development of type 2 diabetes. It is well accepted that beta cell dysfunction is required for hyperglycaemia to occur. The prevailing view is that, in the presence of insulin resistance, beta cell dysfunction that occurs early in the course of the disease process is the critical abnormality. An alternative model has been proposed in which primary beta cell overstimulation results in insulin hypersecretion that then leads to the development of obesity and insulin resistance, and ultimately to beta cell exhaustion. In this review, data from preclinical and clinical studies, including intervention studies, are discussed in the context of these models. The preponderance of the data supports the view that an early beta cell functional defect is the more likely mechanism underlying the pathogenesis of hyperglycaemia in the majority of individuals who develop type 2 diabetes. Graphical abstract.
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Disruption of fasting and post-load glucose homeostasis are largely independent and sustained by distinct and early major beta-cell function defects: a cross-sectional and longitudinal analysis of the Relationship between Insulin Sensitivity and Cardiovascular risk (RISC) study cohort.
Mengozzi, A, Tricò, D, Nesti, L, Petrie, J, Højlund, K, Mitrakou, A, Krebs, M, Mari, A, Natali, A, ,
Metabolism: clinical and experimental. 2020;:154185
Abstract
BACKGROUND/AIMS: Uncertainty still exists on the earliest beta-cell defects at the bases of the type 2 diabetes. We assume that this depends on the inaccurate distinction between fasting and post-load glucose homeostasis and aim at providing a description of major beta-cell functions across the full physiologic spectrum of each condition. METHODS In 1320 non-diabetic individuals we performed an OGTT with insulin secretion modeling and a euglycemic insulin clamp, coupled in subgroups to glucose tracers and IVGTT; 1038 subjects underwent another OGTT after 3.5 years. Post-load glucose homeostasis was defined as mean plasma glucose above fasting levels (δOGTT). The analysis was performed by two-way ANCOVA. RESULTS Fasting plasma glucose (FPG) and δOGTT were weakly related variables (stβ = 0.12) as were their changes over time (r = -0.08). Disruption of FPG control was associated with an isolated and progressive decline (approaching 60%) of the sensitivity of the beta-cell to glucose values within the normal fasting range. Disruption of post-load glucose control was characterized by a progressive decline (approaching 60%) of the slope of the full beta-cell vs glucose dose-response curve and an early minor (30%) decline of potentiation. The acute dynamic beta-cell responses, neither per se nor in relation to the degree of insulin resistance appeared to play a relevant role in disruption of fasting or post-load homeostasis. Follow-up data qualitatively and quantitatively confirmed the results of the cross-sectional analysis. CONCLUSION In normal subjects fasting and post-load glucose homeostasis are largely independent, and their disruption is sustained by different and specific beta-cell defects.
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Small changes in glucose variability induced by low and high glycemic index diets are not associated with changes in β-cell function in adults with pre-diabetes.
Utzschneider, KM, Johnson, TN, Breymeyer, KL, Bettcher, L, Raftery, D, Newton, KM, Neuhouser, ML
Journal of diabetes and its complications. 2020;(8):107586
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Abstract
Oscillating glucose levels can increase oxidative stress and may contribute to β-cell dysfunction. We tested the hypothesis that increased glycemic variability contributes to β-cell dysfunction by experimentally altering glucose variability with controlled diets varying in glycemic index (GI). Fifty-two adults with prediabetes received a 2-week moderate GI (GI = 55-58) control diet followed by randomization to a four-week low GI (LGI: GI < 35) or high GI (HGI HI > 70) diet. Those on the HGI diet were randomized to placebo or the antioxidant N-acetylcysteine (NAC). Participants underwent blinded CGMS, fasting oxidative stress markers and an intravenous glucose tolerance test to estimate β-cell function (disposition index: DI). On the control diet, DI was inversely correlated with SD glucose (r = -0.314, p = 0.03), but neither DI nor glucose variability were associated with oxidative stress markers. The LGI diet decreased SD glucose (Control 0.96 ± 0.08 vs. LGI 0.79 ± 0.06, p = 0.02) while the HGI diet increased it (Control 0.88 ± 0.06 vs. HGI 1.06 ± 0.07, p = 0.03). Neither DI nor oxidative stress markers changed after the LGI or HGI diets. NAC had no effect on DI, glucose variability or oxidative stress markers. We conclude small changes in glucose variability induced by dietary GI in adults with pre-diabetes are unlikely to contribute to β-cell dysfunction.
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Cross-Sectional and Longitudinal Examination of Insulin Sensitivity and Secretion across Puberty among Non-Hispanic Black and White Children.
Marwitz, SE, Gaines, MV, Brady, SM, Mi, SJ, Broadney, MM, Yanovski, SZ, Hubbard, VS, Yanovski, JA
Endocrinology and metabolism (Seoul, Korea). 2020;(4):847-857
Abstract
BACKGROUND Few studies using criterion measures of insulin sensitivity (SI) and insulin secretory capacity (ISC) have been conducted across puberty to adulthood. We examined how SI and ISC change from pre-puberty through adulthood. METHODS Hyperglycemic clamp studies were performed in a convenience sample of non-Hispanic Black (NHB) and White children evaluated at age 6 to 12 years and at approximately 5-year intervals into adulthood (maximum age 27 years). SI and ISC (first-phase and steady-state insulin secretion) were determined cross-sectionally in 133 unique participants across puberty and in adulthood. Additionally, longitudinal changes in SI and ISC were compared at two timepoints among three groups defined by changes in pubertal development: pre-pubertal at baseline and late-pubertal at follow-up (n=27), early-pubertal at baseline and late-pubertal at follow-up (n=27), and late-pubertal at baseline and adult at follow-up (n=24). RESULTS Cross-sectionally, SI was highest in pre-puberty and early puberty and lowest in mid-puberty (analysis of covariance [ANCOVA] P=0.001). Longitudinally, SI decreased from pre-puberty to late puberty (P<0.001), then increased somewhat from late puberty to adulthood. Cross-sectionally, first-phase and steady-state ISC increased during puberty and decreased in adulthood (ANCOVA P<0.02). Longitudinally, steady-state and first-phase ISC increased from pre-puberty to late puberty (P<0.007), and steady-state ISC decreased from late puberty to adulthood. The NHB group had lower SI (P=0.003) and greater first-phase and steady-state ISC (P≤0.001), independent of pubertal development. CONCLUSION This study confirms that SI decreases and ISC increases transiently during puberty and shows that these changes largely resolve in adulthood.
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Adding vitamin D3 to the dipeptidyl peptidase-4 inhibitor saxagliptin has the potential to protect β-cell function in LADA patients: A 1-year pilot study.
Zhang, Z, Yan, X, Wu, C, Pei, X, Li, X, Wang, X, Niu, X, Jiang, H, Zeng, X, Zhou, Z
Diabetes/metabolism research and reviews. 2020;(5):e3298
Abstract
AIMS: This trial was conducted to explore the protective effect on β-cell function of adding vitamin D3 to DPP-4 inhibitors to treat patients with latent autoimmune diabetes in adults (LADA). METHODS 60 LADA patients were randomized to group A (n = 21) - conventional therapy with metformin (1-1.7 g/day) and/or insulin treatment; group B (n = 20) - saxagliptin (5 mg/day) plus conventional therapy; and group C (n = 19) - vitamin D3 (2000 IU/day) plus saxagliptin and conventional therapy for 12 months. Fasting and 2-hour postprandial blood samples were collected to measure blood glucose, glycosylated hemoglobin and C-peptide levels at baseline and after 3, 6 and 12 months of treatment. RESULTS During the 12 months of follow-up, the levels of fasting C-peptide (FCP), 2-hour postprandial C-peptide (PCP) and the C-peptide index (CPI, serum C-peptide-to-plasma glucose level ratio) were maintained in group C. In contrast to those in group A and group B, FCP levels decreased significantly in group B, and CPI levels declined significantly in group A during the 1-year treatment (P < .05). Additionally, the levels of GADA titers in group C significantly decreased compared with those at baseline (P < .05), but no significant differences in GADA titers levels were detected in group A and group B. No significant differences were found among the three groups in the levels of FCP, PCP, the CPI or GADA titers. CONCLUSIONS The data suggested that adding 2000 IU/day vitamin D3 to saxagliptin might preserve β-cell function in patients with LADA.
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Metabolic regulation of calcium signaling in beta cells.
Idevall-Hagren, O, Tengholm, A
Seminars in cell & developmental biology. 2020;:20-30
Abstract
The cytoplasmic Ca2+ concentration ([Ca2+]cyt) regulates a vast number of cellular functions, including insulin secretion from beta cells. The major physiological insulin secretagogue, glucose, triggers [Ca2+]cyt oscillations in beta cells. Synchronization of the oscillations among the beta cells within an islet underlies the generation of pulsatile insulin secretion. This review describes the mechanisms generating [Ca2+]cyt oscillations, the interactions between [Ca2+]cyt and cell metabolism, as well as the contribution of various organelles to the shaping of [Ca2+]cyt signals and insulin secretion. It also discusses how Ca2+ signals are coordinated and spread throughout the islets and data indicating that altered Ca2+ signaling is associated with beta cell dysfunction and development of type 2 diabetes.
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The Role of CD36 in Type 2 Diabetes Mellitus: β-Cell Dysfunction and Beyond.
Moon, JS, Karunakaran, U, Suma, E, Chung, SM, Won, KC
Diabetes & metabolism journal. 2020;(2):222-233
Abstract
Impaired β-cell function is the key pathophysiology of type 2 diabetes mellitus, and chronic exposure of nutrient excess could lead to this tragedy. For preserving β-cell function, it is essential to understand the cause and mechanisms about the progression of β-cells failure. Glucotoxicity, lipotoxicity, and glucolipotoxicity have been suggested to be a major cause of β-cell dysfunction for decades, but not yet fully understood. Fatty acid translocase cluster determinant 36 (CD36), which is part of the free fatty acid (FFA) transporter system, has been identified in several tissues such as muscle, liver, and insulin-producing cells. Several studies have reported that induction of CD36 increases uptake of FFA in several cells, suggesting the functional interplay between glucose and FFA in terms of insulin secretion and oxidative metabolism. However, we do not currently know the regulating mechanism and physiological role of CD36 on glucolipotoxicity in pancreatic β-cells. Also, the downstream and upstream targets of CD36 related signaling have not been defined. In the present review, we will focus on the expression and function of CD36 related signaling in the pancreatic β-cells in response to hyperglycemia and hyperlipidemia (ceramide) along with the clinical studies on the association between CD36 and metabolic disorders.
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Update of variants identified in the pancreatic β-cell KATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes.
De Franco, E, Saint-Martin, C, Brusgaard, K, Knight Johnson, AE, Aguilar-Bryan, L, Bowman, P, Arnoux, JB, Larsen, AR, Sanyoura, M, Greeley, SAW, et al
Human mutation. 2020;(5):884-905
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Abstract
The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.