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Decreased beta-cell function in breastfeeding obese and non-obese women: A prospective observational study.
Harreiter, J, Vila, G, Leitner, K, Wattar, L, Leutner, M, Worda, C, Bancher-Todesca, D, Kautzky-Willer, A
Clinical nutrition (Edinburgh, Scotland). 2019;(6):2790-2798
Abstract
BACKGROUND & AIMS Obesity is associated with lower breastfeeding rates. The underlying pathophysiological mechanisms are not well-understood, but there is increasing evidence on an association between parameters of maternal glucose metabolism and prolactin concentrations. In this cross-sectional observational study we investigate the relationship between breastfeeding, maternal obesity, and maternal glucose metabolism postpartum with beta cell function as a primary outcome measure. METHODS We investigated 106 women (44% obese) prospectively recruited during the pregnancy, who underwent a 75 g - 2 h oral glucose tolerance test (OGTT) between the 3rd and 5th months postpartum. At this time point, we tested the relationship between breastfeeding status, maternal prolactin concentrations, maternal obesity, and fasting and dynamic indices of glucose metabolism using multivariate logistic regression in a post hoc analysis of prospective observational data. RESULTS During the study visit at a mean of 122 (SE 9.3) days after delivery, 47% of obese women and 68% of non-obese women were breastfeeding (p < 0.05). Lactation and higher prolactin concentrations were associated with lower prepregnancy weight and lower postpartum insulin concentrations. Prehepatic beta-cell function was decreased in both obese (mean (SD); 0.16 (0.04) vs. 0.19 (0.05), p < 0.05) and non-obese (0.12 (0.05) vs. 0.16 (0.06), p < 0.01), lactating women. Obese lactating women have significantly lower first (1135.1 (306.7) pmol/L vs. 1517.3 (475.8) pmol/L, p < 0.01) and second phase insulin secretion (mean (SD), 300.2 (70.7) pmol/L vs. 393.1 (115.5) pmol/L, p < 0.01) as shown by Stumvoll indices when comparing to obese non-lactating women. Prehepatic beta-cell function and Stumvoll 1st phase insulin secretion index, but not BMI, were independently and negatively associated with breastfeeding and circulating prolactin concentrations. CONCLUSIONS Beta-cell function during lactation relates to breastfeeding and circulating prolactin concentrations independently of obesity. The well-known positive effects of lactation on maternal and offspring outcomes might reflect a causative relationship of higher breastfeeding rates in metabolically healthier women.
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SYNDROMES OF KETOSIS-PRONE DIABETES.
Balasubramanyam, A
Transactions of the American Clinical and Climatological Association. 2019;:145-155
Abstract
Ketosis-prone diabetes (KPD) is a heterogeneous condition characterized by patients who present with diabetic ketoacidosis but lack the phenotype of autoimmune type 1 diabetes. Here I review progress in our understanding of KPD and its place in the expanding universe of "atypical diabetes." I focus on investigations of our collaborative research group at Baylor College of Medicine and the University of Washington using a longitudinally followed, heterogeneous, multiethnic cohort of KPD patients. We have identified clinically and pathophysiologically distinct KPD subgroups, separable by the presence or absence of islet autoimmunity and the presence or absence of beta cell functional reserve. The resulting "Aß" classification of KPD accurately predicts long-term glycemic control and insulin dependence. I describe key characteristics of the KPD subgroups, their natural histories, and our investigations into their immunologic, genetic, and metabolic etiologies. These studies serve as a paradigm for the investigation of atypical forms of diabetes.
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Effect of vitamin D3 supplementation on insulin resistance and β-cell function in prediabetes: a double-blind, randomized, placebo-controlled trial.
Wallace, HJ, Holmes, L, Ennis, CN, Cardwell, CR, Woodside, JV, Young, IS, Bell, PM, Hunter, SJ, McKinley, MC
The American journal of clinical nutrition. 2019;(5):1138-1147
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Abstract
BACKGROUND Observational studies have suggested an inverse association between low serum 25-hydroxyvitamin D [25(OH)D] concentrations and development of type 2 diabetes. High-quality trials are required to test the hypothesis that vitamin D is a direct contributor to type 2 diabetes pathogenesis. OBJECTIVE The purpose of this double-blind randomized placebo-controlled trial was to investigate the effect of vitamin D3 supplementation on insulin resistance (IR) and β-cell function in people with prediabetes and suboptimal vitamin D status (<50 nmol/L). METHODS Sixty-six individuals were randomly assigned to receive 3000 IU (75 µg) vitamin D3 or placebo daily for 26 wk. Compliance was monitored by pill count and change in serum 25(OH)D concentration using LC-MS. The primary endpoint was between-group difference in change in IR assessed using a 2-step euglycemic-hyperinsulinemic clamp combined with infusion of tritiated glucose. An oral-glucose-tolerance test was performed pre- and postintervention to calculate indices of β-cell function. Between-group comparisons were made using ANCOVA. RESULTS In total, 64 participants completed the study. Baseline serum 25(OH)D concentrations in the vitamin D3 and placebo group were 30.7 and 30.0 nmol/L, with status increasing by 70.5 nmol/L and 5.3 nmol/L, respectively (between-group difference in vitamin D: 65.8 nmol/L; 95% CI: 54.2, 77.3 nmol/L; P < 0.01), after supplementation. There was no difference between groups in measures of whole-body, peripheral, or hepatic IR or in any measure of glycemic control or β-cell function. CONCLUSION This study employed a robust assessment of IR and β-cell function and targeted a high-risk population with low 25(OH)D status at baseline and found that vitamin D3 supplementation had no effect on insulin action in people with prediabetes.This trial was registered on clinicaltrials.gov as NCT01889810.
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Cholesterol metabolism, pancreatic β-cell function and diabetes.
Perego, C, Da Dalt, L, Pirillo, A, Galli, A, Catapano, AL, Norata, GD
Biochimica et biophysica acta. Molecular basis of disease. 2019;(9):2149-2156
Abstract
Cholesterol plays an essential role in determining cell membrane physico-chemical characteristics and functions. A proper membrane structure is critical in pancreatic β-cells for glucose-mediated insulin secretion, and alterations in cellular cholesterol content may negatively affect this process, leading to β-cell dysfunction. The low density lipoprotein receptor (LDL-R) appears to play a relevant role in ß-cell dysfunction due to cholesterol accumulation. This observation raised the question of whether hypocholesterolemic drugs which increase LDL-R expression might bear diabetogenic properties, thus increasing the risk of new-onset diabetes or worsen glycaemic parameters in diabetic patients. Being at higher cardiovascular risk, diabetic patients are usually treated with hypolipidemic drugs to correct the atherogenic dyslipidemia characteristic of this pathological condition. Statin therapy has been associated with an increased incidence of new-onset diabetes (NOD), being the diabetogenic effect depending on the type and dose of statin. However, it is worth noting that the benefits on cardiovascular mortality largely exceed the increased risk associated with the development of diabetes. Although genetic variants associated with lower levels of LDL-C are also associated with an increased NOD risk, clinical trials with lipid-lowering drugs other than statins, namely ezetimibe or monoclonal antibodies against PCSK9, did not observe an increase of developing diabetes. In summary, molecular evidence clearly points to a key role for cholesterol homeostasis in pancreatic β-cell function which, in humans, is negatively affected by statins. Available data exclude that this could be the case for other hypocholesterolemic approaches, but long-term studies are warranted to explore this critical aspect.
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Biogenesis of the Insulin Secretory Granule in Health and Disease.
Guest, PC
Advances in experimental medicine and biology. 2019;:17-32
Abstract
The secretory granules of pancreatic beta cells are specialized organelles responsible for the packaging, storage and secretion of the vital hormone insulin. The insulin secretory granules also contain more than 100 other proteins including the proteases involved in proinsulin-to insulin conversion, other precursor proteins, minor co-secreted peptides, membrane proteins involved in cell trafficking and ion translocation proteins essential for regulation of the intragranular environment. The synthesis, transport and packaging of these proteins into nascent granules must be carried out in a co-ordinated manner to ensure correct functioning of the granule. The process is regulated by many circulating nutrients such as glucose and can change under different physiological states. This chapter discusses the various processes involved in insulin granule biogenesis with a focus on the granule composition in health and disease.
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Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 diabetes.
Cusi, K, Bril, F, Barb, D, Polidori, D, Sha, S, Ghosh, A, Farrell, K, Sunny, NE, Kalavalapalli, S, Pettus, J, et al
Diabetes, obesity & metabolism. 2019;(4):812-821
Abstract
AIM: To evaluate the impact of the sodium glucose co-transporter 2 inhibitor canagliflozin on intrahepatic triglyceride (IHTG) accumulation and its relationship to changes in body weight and glucose metabolism. MATERIALS AND METHODS In this double-blind, parallel-group, placebo-controlled, 24-week trial subjects with inadequately controlled type 2 diabetes mellitus (T2DM; HbA1c = 7.7% ± 0.7%) from two centres were randomly assigned (1:1) to canagliflozin 300 mg or placebo. We measured IHTG by proton-magnetic resonance spectroscopy (primary outcome), hepatic/muscle/adipose tissue insulin sensitivity during a 2-step euglycaemic insulin clamp, and beta-cell function during a mixed meal tolerance test. Analyses were per protocol. RESULTS Between 8 September 2014-13 June 2016, 56 patients were enrolled. Canagliflozin reduced HbA1c (placebo-subtracted change: -0.71% [-1.08; -0.33]) and body weight (-3.4% [-5.4; -1.4]; both P ≤ 0.001). A numerically larger absolute decrease in IHTG occurred with canagliflozin (-4.6% [-6.4; -2.7]) versus placebo (-2.4% [-4.2; -0.6]; P = 0.09). In patients with non-alcoholic fatty liver disease (n = 37), the decrease in IHTG was -6.9% (-9.5; -4.2) versus -3.8% (-6.3; -1.3; P = 0.05), and strongly correlated with the magnitude of weight loss (r = 0.69, P < 0.001). Body weight loss ≥5% with a ≥30% relative reduction in IHTG occurred more often with canagliflozin (38% vs. 7%, P = 0.009). Hepatic insulin sensitivity improved with canagliflozin (P < 0.01), but not muscle or adipose tissue insulin sensitivity. Beta-cell glucose sensitivity, insulin clearance, and disposition index improved more with canagliflozin (P < 0.05). CONCLUSIONS Canagliflozin improves hepatic insulin sensitivity and insulin secretion and clearance in patients with T2DM. IHTG decreases in proportion to the magnitude of body weight loss, which tended to be greater and occur more often with canagliflozin.
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Selenium supplementation and insulin resistance in a randomized, clinical trial.
Jacobs, ET, Lance, P, Mandarino, LJ, Ellis, NA, Chow, HS, Foote, J, Martinez, JA, Hsu, CP, Batai, K, Saboda, K, et al
BMJ open diabetes research & care. 2019;(1):e000613
Abstract
OBJECTIVE While controversial, observational and randomized clinical trial data implicate the micronutrient selenium (Se) in the development of type 2 diabetes (T2D). The aim of this study was to test the hypothesis that Se supplementation adversely affects pancreatic β-cell function and insulin sensitivity. RESEARCH DESIGN AND METHODS In a subset of 400 individuals participating in a randomized, placebo-controlled trial of Se at 200 µg/day for colorectal adenomatous polyps, fasting plasma glucose and insulin were measured before randomization and within 6 months of completing intervention. Change in the homeostasis model assessment-β cell function (HOMA2-%β) and insulin sensitivity (HOMA2-%S) were compared between arms. A subgroup of 175 (79 Se and 96 placebo) participants underwent a modified oral glucose tolerance test (mOGTT) at the end of intervention and change in glucose values was assessed. RESULTS No statistically significant differences were observed for changes in HOMA2-%β or HOMA2-%S between those who received Se compared with placebo. After a mean of 2.9 years on study, mean HOMA2-%β values were 3.1±24.0 and 3.1±29.8 for the Se and placebo groups, respectively (p=0.99). For HOMA2-%S, the values were -0.5±223.2 and 80.9±1530.9 for the Se and placebo groups, respectively (p=1.00). Stratification by sex or age did not reveal any statistically significant effects on insulin sensitivity by treatment group. For mOGTT, mean baseline fasting blood glucose concentrations were significantly higher among participants in the placebo group compared with the Se group (96.6±14.6 and 92.3±12.0, respectively; p=0.04), a trend which remained through the 20 min assessment. CONCLUSIONS These findings do not support a significant adverse effect of daily Se supplementation with 200 µg/day of selenized yeast on β-cell function or insulin sensitivity as an explanation for previously reported associations between Se and T2D. Further clarification of longer term effects of Se is needed. CLINICAL TRIAL REGISTRY NIH Clinical Trials.gov number NCT00078897.
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Mixed-meal tolerance test to assess residual beta-cell secretion: Beyond the area-under-curve of plasma C-peptide concentration.
Ruan, Y, Willemsen, RH, Wilinska, ME, Tauschmann, M, Dunger, DB, Hovorka, R
Pediatric diabetes. 2019;(3):282-285
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AIMS: Residual beta-cell secretion in type 1 diabetes is commonly assessed by area-under-curve of plasma C-peptide concentration (AUCCpep ) following mixed-meal tolerance test (MMTT). We aimed to investigate alternative measures of beta-cell responsiveness. METHODS We analyzed data from 32 youth (age 7 to 17 years) undergoing MMTT within 6 months of type 1 diabetes diagnosis. We related AUCCpep with (a) validated mechanistic index of postprandial beta-cell responsiveness MI accounting for glucose level during MMTT, and (b) pragmatic marker calculated as baseline plasma C-peptide concentration corrected for baseline plasma glucose concentration. RESULTS Postprandial responsiveness MI was correlated with age and BMI SDS (Rs = 0.66 and 0.44, P < 0.01 and P < 0.05) and was more correlated with glycated hemoglobin than AUCCpep (Rs = 0.79, P = 0.04). The pragmatic marker was highly correlated with AUCCpep (Rs = 0.94, P < 0.01). CONCLUSIONS Postprandial responsiveness MI may be more relevant to glucose control than AUCCpep . Baseline C-peptide corrected for baseline glucose appears to be a suitable surrogate of AUCCpep if MMTT is not performed.
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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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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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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.