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1.
Reducing Cholesterol and Fat Intake Improves Glucose Tolerance by Enhancing β Cell Function in Nondiabetic Subjects.
Tricò, D, Trifirò, S, Mengozzi, A, Morgantini, C, Baldi, S, Mari, A, Natali, A
The Journal of clinical endocrinology and metabolism. 2018;(2):622-631
Abstract
CONTEXT A diet low in cholesterol and fat is commonly recommended to prevent metabolic and cardiovascular diseases; however, its effect on glucose tolerance is largely unknown. OBJECTIVE We examined whether and by which mechanisms a chronic reduction of cholesterol and fat intake affects glucose tolerance in nondiabetic individuals, independently of weight changes. DESIGN AND PARTICIPANTS In this crossover, randomized clinical trial, 30 healthy subjects, including 15 with family history of type 2 diabetes (T2D) (T2D offspring), underwent a 75-g oral glucose tolerance test (OGTT) after two 14-day isocaloric high-cholesterol, high-fat (HChF) or low-cholesterol, and low-fat (LChF) diets. MAIN OUTCOME MEASURES We evaluated changes in glucose tolerance, β cell function, insulin clearance, and insulin sensitivity by modeling plasma glucose, insulin, and C-peptide levels during the OGTT. RESULTS The shift from the HChF to the LChF diet was neutral on body weight but increased glucose tolerance (mean glucose -5%, P = 0.01) and three components of β cell function: glucose sensitivity (+17%, P = 0.01), insulin secretion at fasting glucose (+20%, P = 0.02), and potentiation (+19%, P = 0.03). The LChF diet improved insulin sensitivity (+7%, P = 0.048) only in T2D offspring, who tended to be more susceptible to the positive effect of the diet on glucose tolerance. CONCLUSIONS A chronic and isocaloric decrease in dietary cholesterol and fat intake improves glucose tolerance by diffusely ameliorating β cell function in nondiabetic subjects. Individuals genetically predisposed to develop T2D tend to be more susceptible to the positive effect of this dietary intervention on glucose tolerance and insulin sensitivity.
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2.
Performance of individually measured vs population-based C-peptide kinetics to assess β-cell function in the presence and absence of acute insulin resistance.
Varghese, RT, Dalla Man, C, Laurenti, MC, Piccinini, F, Sharma, A, Shah, M, Bailey, KR, Rizza, RA, Cobelli, C, Vella, A
Diabetes, obesity & metabolism. 2018;(3):549-555
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Abstract
AIMS: To compare the performance of population-based kinetics with that of directly measured C-peptide kinetics when used to calculate β-cell responsivity indices, and to study people with and without acute insulin resistance to ensure that population-based kinetics apply to all conditions where β-cell function is measured. METHODS Somatostatin was used to inhibit endogenous insulin secretion in 56 people without diabetes. Subsequently, a C-peptide bolus was administered and the changing concentrations were used to calculate individual kinetic measures of C-peptide clearance. In addition, the participants were studied on 2 occasions in random order using an oral glucose tolerance test (OGTT). On one occasion, free fatty acid elevation, to cause insulin resistance, was achieved by infusion of Intralipid + heparin. The Disposition Index (DI) was then estimated by the oral minimal model using either population-based or individual C-peptide kinetics. RESULTS There were marked differences in the exchange variables (k 12 and k 21 ) of the model describing C-peptide kinetics, but smaller differences in the fractional clearance; that is, the irreversible loss from the accessible compartment (k 01 ), obtained from population-based estimates compared with experimental measurement. Because it is predominantly influenced by k 01 , DI estimated using individual kinetics correlated well with DI estimated using population-based kinetics. CONCLUSIONS These data support the use of population-based measures of C-peptide kinetics to estimate β-cell function during an OGTT.
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The α-cell in diabetes mellitus.
Gromada, J, Chabosseau, P, Rutter, GA
Nature reviews. Endocrinology. 2018;(12):694-704
Abstract
Findings from the past 10 years have placed the glucagon-secreting pancreatic α-cell centre stage in the development of diabetes mellitus, a disease affecting almost one in every ten adults worldwide. Glucagon secretion is reduced in patients with type 1 diabetes mellitus, increasing the risk of insulin-induced hypoglycaemia, but is enhanced in type 2 diabetes mellitus, exacerbating the effects of diminished insulin release and action on blood levels of glucose. A better understanding of the mechanisms underlying these changes is therefore an important goal. RNA sequencing reveals that, despite their opposing roles in the control of blood levels of glucose, α-cells and β-cells have remarkably similar patterns of gene expression. This similarity might explain the fairly facile interconversion between these cells and the ability of the α-cell compartment to serve as a source of new β-cells in models of extreme β-cell loss that mimic type 1 diabetes mellitus. Emerging data suggest that GABA might facilitate this interconversion, whereas the amino acid glutamine serves as a liver-derived factor to promote α-cell replication and maintenance of α-cell mass. Here, we survey these developments and their therapeutic implications for patients with diabetes mellitus.
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Effect of single-dose DPP-4 inhibitor sitagliptin on β-cell function and incretin hormone secretion after meal ingestion in healthy volunteers and drug-naïve, well-controlled type 2 diabetes subjects.
Alsalim, W, Göransson, O, Carr, RD, Bizzotto, R, Tura, A, Pacini, G, Mari, A, Ahrén, B
Diabetes, obesity & metabolism. 2018;(4):1080-1085
Abstract
To explore the effects of a single dose of the DPP-4 inhibitor sitagliptin on glucose-standardized insulin secretion and β-cell glucose sensitivity after meal ingestion, 12 healthy and 12 drug-naïve, well-controlled type 2 diabetes (T2D) subjects (mean HbA1c 43 mmol/mol, 6.2%) received sitagliptin (100 mg) or placebo before a meal (525 kcal). β-cell function was measured as the insulin secretory rate at a standardized glucose concentration and the β-cell glucose sensitivity (the slope between glucose and insulin secretory rate). Incretin levels were also monitored. Sitagliptin increased standardized insulin secretion, in both healthy and T2D subjects, compared to placebo, but without increasing β-cell glucose sensitivity. Sitagliptin also increased active glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) and reduced total (reflecting the secretion) GIP, but not total GLP-1 levels. We conclude that a single dose of DPP-4 inhibition induces dissociated effects on different aspects of β-cell function and incretin hormones after meal ingestion in both healthy and well-controlled T2D subjects.
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Association of free-living physical activity measures with metabolic phenotypes in type 2 diabetes at the time of diagnosis. The Verona Newly Diagnosed Type 2 Diabetes Study (VNDS).
Dauriz, M, Bacchi, E, Boselli, L, Santi, L, Negri, C, Trombetta, M, Bonadonna, RC, Bonora, E, Moghetti, P
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2018;(4):343-351
Abstract
BACKGROUND AND AIM Lifestyle is considered a major determinant of risk of type 2 diabetes (T2D). We investigated whether daily physical activity (DPA) is associated with beta-cell function (BF) and/or insulin sensitivity (IS) in patients with T2D at the time of diagnosis. METHODS AND RESULTS In 41 subjects enrolled in the Verona Newly-Diagnosed Type 2 Diabetes Study we assessed: (1) IS, by euglycaemic insulin clamp; (2) BF, estimated by prolonged-OGTT minimal modeling and expressed as derivative and proportional control; (3) DPA and energy expenditure (EE), assessed over 48-h monitoring by a validated wearable armband system. Study participants (median [IQR]; age: 62 [53-67] years, BMI: 30.8 [26.5-34.3] Kg m-2, HbA1c: 6.7 [6.3-7.3]%; 49.7 [45.4-56.3] mmol/mol) were moderately active (footsteps/day: 7773 [5748-10,927]; DPA≥3MET: 70 [38-125] min/day), but none of them exercised above 6 metabolic equivalents (MET). EE, expressed as EETOT (total daily-EE) and EE≥3MET (EE due to DPA≥3MET) were 2398 [2226-2801] and 364 [238-617] Kcal/day, respectively. IS (M-clamp 630 [371-878] μmol/min/m2) was positively associated with DPA and EE, independent of age, sex and BMI (p < 0.05). Among the DPA and EE parameters assessed, DPA≥3MET and EETOT were independent predictors of IS in multivariable regression analyses, adjusted for age, sex, BMI (R2 = 16%, R2 = 19%, respectively; p < 0.01). None of model-derived components of BF was significantly associated with DPA or accompanying EE. CONCLUSIONS Our study highlighted moderate levels of DPA and total EE as potential determinants of IS, but not BF, in T2D at the time of diagnosis. Intervention studies are needed to conclusively elucidate the effect of DPA on these features. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER NCT01526720.
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Dipeptidyl peptidase-4 inhibitors (DPP-4i) combined with vitamin D3: An exploration to treat new-onset type 1 diabetes mellitus and latent autoimmune diabetes in adults in the future.
Pinheiro, MM, Pinheiro, FMM, Trabachin, ML
International immunopharmacology. 2018;:11-17
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by destruction of pancreatic beta cells through cell injury caused primarily by cytotoxic T lymphocytes (CD8+). The pathophysiological basis of T1DM seems to be an imbalance between a reduced function of T regulatory lymphocytes and an increased inflammatory activity of Th17 lymphocytes caused by increased production of inflammatory cytokines, as IL-1β, IL-6, IL-17 and IFN-gamma due to environmental factors and genetic predisposition. The preservation of the reserve of beta cells in new-onset T1DM and latent autoimmune diabetes in adults (LADA) by immunomodulation in addition to the incretin effect seems to be possible with an association of DPP-4 inhibitors and vitamin D3. In this review, we discuss the effects of both drugs on the immune system and on beta cell function and their eventual additive effects in preserving the residual function of beta cells in new-onset T1DM and LADA.
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Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent upon Capacity for β Cell Recovery.
Taylor, R, Al-Mrabeh, A, Zhyzhneuskaya, S, Peters, C, Barnes, AC, Aribisala, BS, Hollingsworth, KG, Mathers, JC, Sattar, N, Lean, MEJ
Cell metabolism. 2018;(4):547-556.e3
Abstract
The Diabetes Remission Clinical Trial reported return and persistence of non-diabetic blood glucose control in 46% of people with type 2 diabetes of up to 6 years duration. Detailed metabolic studies were performed on a subgroup (intervention, n = 64; control, n = 26). In the intervention group, liver fat content decreased (16.0% ± 1.3% to 3.1% ± 0.5%, p < 0.0001) immediately after weight loss. Similarly, plasma triglyceride and pancreas fat content decreased whether or not glucose control normalized. Recovery of first-phase insulin response (0.04[-0.05-0.32] to 0.11[0.0005-0.51] nmol/min/m2, p < 0.0001) defined those who returned to non-diabetic glucose control and this was durable at 12 months (0.11[0.005-0.81] nmol/min/m2, p = 0.0001). Responders were similar to non-responders at baseline but had shorter diabetes duration (2.7 ± 0.3 versus 3.8 ± 0.4 years; p = 0.02). This study demonstrates that β cell ability to recover long-term function persists after diagnosis, changing the previous paradigm of irreversible loss of β cell function in type 2 diabetes.
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The effects of kisspeptin on β-cell function, serum metabolites and appetite in humans.
Izzi-Engbeaya, C, Comninos, AN, Clarke, SA, Jomard, A, Yang, L, Jones, S, Abbara, A, Narayanaswamy, S, Eng, PC, Papadopoulou, D, et al
Diabetes, obesity & metabolism. 2018;(12):2800-2810
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Abstract
AIMS: To investigate the effect of kisspeptin on glucose-stimulated insulin secretion and appetite in humans. MATERIALS AND METHODS In 15 healthy men (age: 25.2 ± 1.1 years; BMI: 22.3 ± 0.5 kg m-2 ), we compared the effects of 1 nmol kg-1 h-1 kisspeptin versus vehicle administration on glucose-stimulated insulin secretion, metabolites, gut hormones, appetite and food intake. In addition, we assessed the effect of kisspeptin on glucose-stimulated insulin secretion in vitro in human pancreatic islets and a human β-cell line (EndoC-βH1 cells). RESULTS Kisspeptin administration to healthy men enhanced insulin secretion following an intravenous glucose load, and modulated serum metabolites. In keeping with this, kisspeptin increased glucose-stimulated insulin secretion from human islets and a human pancreatic cell line in vitro. In addition, kisspeptin administration did not alter gut hormones, appetite or food intake in healthy men. CONCLUSIONS Collectively, these data demonstrate for the first time a beneficial role for kisspeptin in insulin secretion in humans in vivo. This has important implications for our understanding of the links between reproduction and metabolism in humans, as well as for the ongoing translational development of kisspeptin-based therapies for reproductive and potentially metabolic conditions.
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Changes Over Time in Hepatic Markers Predict Changes in Insulin Sensitivity, β-Cell Function, and Glycemia.
Pinnaduwage, L, Ye, C, Hanley, AJ, Connelly, PW, Sermer, M, Zinman, B, Retnakaran, R
The Journal of clinical endocrinology and metabolism. 2018;(7):2651-2659
Abstract
CONTEXT Serum concentrations of liver enzymes and the hepatokine fetuin-A have been linked to the risk of type 2 diabetes, but their longitudinal impact on insulin resistance and β-cell dysfunction is unclear. OBJECTIVE To evaluate the impact of changes over 2 years in fetuin-A and the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyltransferase (GGT) on changes in insulin sensitivity, β-cell function, and glycemia in women with varying degrees of previous gestational dysglycemia, reflecting a range of future diabetic risk. DESIGN/SETTING/PARTICIPANTS In total, 336 women underwent glucose challenge test (GCT) and oral glucose tolerance test (OGTT) in pregnancy, followed by repeat OGTT and measurement of ALT/AST/GGT/fetuin-A at both 1 year and 3 years postpartum. The antepartum GCT/OGTT identified four gestational glucose tolerance groups: gestational diabetes (n = 104), gestational impaired glucose tolerance (n = 59), abnormal GCT with normal OGTT (n = 98), and normal GCT/OGTT (n = 75). RESULTS At 1 and 3 years postpartum, ALT, AST, GGT, and fetuin-A did not differ across the four groups, but the intervening change in ALT/AST ratio was greater in the gestational dysglycemia groups (P = 0.05). Higher baseline ALT/AST (t = -1.99, P = 0.05) and fetuin-A (t = -3.17, P = 0.002) predicted lower insulin sensitivity (Matsuda) at 3 years, as did their respective changes from 1 to 3 years (ALT/AST: t = -5.47, P < 0.0001; fetuin-A: t = -3.56, P = 0.0004). Change in ALT/AST predicted lower β-cell function (t = -2.33, P = 0.02) and higher fasting glucose at 3 years (t = 2.55, P = 0.01). Moreover, baseline fetuin-A predicted prediabetes/diabetes at 3 years (OR, 1.38; 95% CI, 1.01 to 1.88). CONCLUSION Circulating hepatic markers, particularly ALT/AST ratio and fetuin-A, track with changes in insulin sensitivity and β-cell function, supporting a pathophysiologic basis in their prediction of diabetic risk.
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Impact of prematurity for pancreatic islet and beta-cell development.
Bloomfield, FH
The Journal of endocrinology. 2018;(3):R161-R171
Abstract
As increasing numbers of babies born preterm survive into adulthood, it is becoming clear that, in addition to the well-described risks of neurodevelopmental sequelae, there also are increased risks for non-communicable diseases, including diabetes. Epidemiological studies indicate that risks are increased even for birth at late preterm and early term gestations and for both type 1 and type 2 diabetes. Thus, factors related to preterm birth likely affect development of the fetal and neonatal beta-cell in addition to effects on peripheral insulin sensitivity. These factors could operate prior to preterm birth and be related to the underlying cause of preterm birth, to the event of being born preterm itself, to the postnatal care of the preterm neonate or to a combination of these exposures. Experimental evidence indicates that factors may be operating during all these critical periods to contribute to altered development of beta-cell mass in those born preterm. Greater understanding of how these factors impact upon development of the pancreas may lead to interventions or management approaches that mitigate the increased risk of later diabetes.