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Hepatic Lipoprotein Export and Remission of Human Type 2 Diabetes after Weight Loss.
Al-Mrabeh, A, Zhyzhneuskaya, SV, Peters, C, Barnes, AC, Melhem, S, Jesuthasan, A, Aribisala, B, Hollingsworth, KG, Lietz, G, Mathers, JC, et al
Cell metabolism. 2020;(2):233-249.e4
Abstract
The role of hepatic lipoprotein metabolism in diet-induced remission of type 2 diabetes is currently unclear. Here, we determined the contributions of hepatic VLDL1-triglyceride production rate and VLDL1-palmitic acid content to changes in intra-pancreatic fat and return of first phase insulin response in a subgroup of the Diabetes Remission Clinical Trial. Liver fat, VLDL1-triglyceride production, and intra-pancreatic fat decreased after weight loss and remained normalized after 24 months of remission. First-phase insulin response remained increased only in those maintaining diabetes remission. Compared with those in remission at 24 months, individuals who relapsed after initial remission had a greater rise in the content of VLDL1-triglyceride and VLDL1-palmitic acid, re-accumulated intra-pancreatic fat, and lost first-phase response by 24 months. Thus, we observed temporal relationships between VLDL1-triglyceride production, hepatic palmitic acid flux, intra-pancreatic fat, and β-cell function. Weight-related disordered fat metabolism appears to drive development and reversal of type 2 diabetes.
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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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Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol.
Lim, EL, Hollingsworth, KG, Aribisala, BS, Chen, MJ, Mathers, JC, Taylor, R
Diabetologia. 2011;(10):2506-14
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Abstract
AIMS/HYPOTHESIS Type 2 diabetes is regarded as inevitably progressive, with irreversible beta cell failure. The hypothesis was tested that both beta cell failure and insulin resistance can be reversed by dietary restriction of energy intake. METHODS Eleven people with type 2 diabetes (49.5 ± 2.5 years, BMI 33.6 ± 1.2 kg/m(2), nine male and two female) were studied before and after 1, 4 and 8 weeks of a 2.5 MJ (600 kcal)/day diet. Basal hepatic glucose output, hepatic and peripheral insulin sensitivity and beta cell function were measured. Pancreas and liver triacylglycerol content was measured using three-point Dixon magnetic resonance imaging. An age-, sex- and weight-matched group of eight non-diabetic participants was studied. RESULTS After 1 week of restricted energy intake, fasting plasma glucose normalised in the diabetic group (from 9.2 ± 0.4 to 5.9 ± 0.4 mmol/l; p = 0.003). Insulin suppression of hepatic glucose output improved from 43 ± 4% to 74 ± 5% (p = 0.003 vs baseline; controls 68 ± 5%). Hepatic triacylglycerol content fell from 12.8 ± 2.4% in the diabetic group to 2.9 ± 0.2% by week 8 (p = 0.003). The first-phase insulin response increased during the study period (0.19 ± 0.02 to 0.46 ± 0.07 nmol min(-1) m(-2); p < 0.001) and approached control values (0.62 ± 0.15 nmol min(-1) m(-2); p = 0.42). Maximal insulin response became supranormal at 8 weeks (1.37 ± 0.27 vs controls 1.15 ± 0.18 nmol min(-1) m(-2)). Pancreatic triacylglycerol decreased from 8.0 ± 1.6% to 6.2 ± 1.1% (p = 0.03). CONCLUSIONS/INTERPRETATION Normalisation of both beta cell function and hepatic insulin sensitivity in type 2 diabetes was achieved by dietary energy restriction alone. This was associated with decreased pancreatic and liver triacylglycerol stores. The abnormalities underlying type 2 diabetes are reversible by reducing dietary energy intake.
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Pioglitazone decreases fasting and postprandial endogenous glucose production in proportion to decrease in hepatic triglyceride content.
Ravikumar, B, Gerrard, J, Dalla Man, C, Firbank, MJ, Lane, A, English, PT, Cobelli, C, Taylor, R
Diabetes. 2008;(9):2288-95
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OBJECTIVE Hepatic triglyceride is closely associated with hepatic insulin resistance and is known to be decreased by thiazolididinediones. We studied the effect of pioglitazone on hepatic triglyceride content and the consequent effect on postprandial endogenous glucose production (EGP) in type 2 diabetes. RESEARCH DESIGN AND METHODS Ten subjects with type 2 diabetes on sulfonylurea therapy were treated with pioglitazone (30 mg daily) for 16 weeks. EGP was measured using a dynamic isotopic methodology after a standard liquid test meal both before and after pioglitazone treatment. Liver and muscle triglyceride levels were measured by (1)H magnetic resonance spectroscopy, and intra-abdominal fat content was measured by magnetic resonance imaging. RESULTS Pioglitazone treatment reduced mean plasma fasting glucose and mean peak postprandial glucose levels. Fasting EGP decreased after pioglitazone treatment (16.6 +/- 1.0 vs. 12.2 +/- 0.7 micromol . kg(-1) . min(-1), P = 0.005). Between 80 and 260 min postprandially, EGP was twofold lower on pioglitazone (2.58 +/- 0.25 vs. 1.26 +/- 0.30 micromol . kg(-1) . min(-1), P < 0.001). Hepatic triglyceride content decreased by approximately 50% (P = 0.03), and muscle (anterior tibialis) triglyceride content decreased by approximately 55% (P = 0.02). Hepatic triglyceride content was directly correlated with fasting EGP (r = 0.64, P = 0.01) and inversely correlated to percentage suppression of EGP (time 150 min, r = -0.63, P = 0.02). Muscle triglyceride, subcutaneous fat, and visceral fat content were not related to EGP. CONCLUSIONS Reduction in hepatic triglyceride by pioglitazone is very closely related to improvement in fasting and postprandial EGP in type 2 diabetes.
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Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies.
Livesey, G, Taylor, R
The American journal of clinical nutrition. 2008;(5):1419-37
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Abstract
BACKGROUND The glycemic response to dietary fructose is low, which may improve concentrations of glycated hemoglobin (HbA(1c), a marker of dysglycemia). Meanwhile, adverse effects on plasma triacylglycerol (a marker of dyslipidemia) and body weight have been questioned. Such effects are reported inconsistently.
OBJECTIVE We aimed to evaluate the effect of fructose on these health markers, particularly examining treatment dose and duration, and level of glycemic control.
DESIGN A literature search was conducted for relevant randomized and controlled intervention studies of crystalline or pure fructose (excluding high-fructose corn syrup), data extraction, meta-analyses, and modeling using meta-regression.
RESULTS Fructose intake < 90 g/d significantly improved HbA(1c) concentrations dependent on the dose, the duration of study, and the continuous severity of dysglycemia throughout the range of dysglycemia. There was no significant change in body weight at intakes <100 g fructose/d. Fructose intakes of <50 g/d had no postprandially significant effect on triacylglycerol and those of
or=100 g fructose/d, the effect on fasting triacylglycerol depended on whether sucrose or starch was being exchanged with fructose, and the effect was dose-dependent but was less with increasing duration of treatment. Different health types and sources of bias were examined; they showed no significant departure from a general trend. CONCLUSIONS The meta-analysis shows that fructose intakes from 0 to >or=90 g/d have a beneficial effect on HbA(1c). Significant effects on postprandial triacylglycerols are not evident unless >50 g fructose/d is consumed, and no significant effects are seen for fasting triacylglycerol or body weight with intakes of