Accumulation of intrapancreatic fat may be important in type 2 diabetes, but widely varying data have been reported. The standard quantification by MRI in vivo is time consuming and dependent upon a ...high level of experience. We aimed to develop a new method which would minimise inter-observer variation and to compare this against previously published datasets.
A technique of 'biopsying' the image to minimise inclusion of non-parenchymal tissues was developed. Additionally, thresholding was applied to exclude both pancreatic ducts and intrusions of visceral fat, with pixels of fat values of <1% or >20% being excluded. The new MR image 'biopsy' (MR-opsy) was compared to the standard method by 6 independent observers with wide experience of image analysis but no experience of pancreas imaging. The effect of the new method was examined on datasets from two studies of weight loss in type 2 diabetes.
At low levels of intrapancreatic fat neither the result nor the inter-observer CV was changed by MR-opsy, thresholding or a combination of the methods. However, at higher levels the conventional method exhibited poor inter-observer agreement (coefficient of variation 26.9%) and the new combined method improved the CV to 4.3% (p<0.03). Using either MR-opsy alone or with thresholding, the new methods indicated a closer relationship between decrease in intrapancreatic fat and fall in blood glucose.
The inter-observer variation for quantifying intrapancreatic fat was substantially improved by the new method when pancreas fat levels were moderately high. The method will improve comparability of pancreas fat measurement between research groups.
Type 2 diabetes mellitus (T2DM) is generally regarded as an irreversible chronic condition. Because a very low-calorie diet (VLCD) can bring about acute return to normal glucose control in some ...people with T2DM, this study tested the potential durability of this normalization. The underlying mechanisms were defined.
People with a T2DM duration of 0.5-23 years (n = 30) followed a VLCD for 8 weeks. All oral agents or insulins were stopped at baseline. Following a stepped return to isocaloric diet, a structured, individualized program of weight maintenance was provided. Glucose control, insulin sensitivity, insulin secretion, and hepatic and pancreas fat content were quantified at baseline, after return to isocaloric diet, and after 6 months to permit the primary comparison of change between post-weight loss and 6 months in responders. Responders were defined as achieving fasting blood glucose <7 mmol/L after return to isocaloric diet.
Weight fell (98.0 ± 2.6 to 83.8 ± 2.4 kg) and remained stable over 6 months (84.7 ± 2.5 kg). Twelve of 30 participants achieved fasting plasma glucose <7 mmol/L after return to isocaloric diet (responders), and 13 of 30 after 6 months. Responders had a shorter duration of diabetes and a higher initial fasting plasma insulin level. HbA1c fell from 7.1 ± 0.3 to 5.8 ± 0.2% (55 ± 4 to 40 ± 2 mmol/mol) in responders (P < 0.001) and from 8.4 ± 0.3 to 8.0 ± 0.5% (68 ± 3 to 64 ± 5 mmol/mol) in nonresponders, remaining constant at 6 months (5.9 ± 0.2 and 7.8 ± 0.3% 41 ± 2 and 62 ± 3 mmol/mol, respectively). The responders were characterized by return of first-phase insulin response.
A robust and sustainable weight loss program achieved continuing remission of diabetes for at least 6 months in the 40% who responded to a VLCD by achieving fasting plasma glucose of <7 mmol/L. T2DM is a potentially reversible condition.
Although impairment in pancreatic insulin secretion is known to precede the clinical diagnosis of type 2 diabetes by up to a decade, fasting blood glucose concentration only rises abnormally once the ...impairment reaches a critical threshold. Despite its centrality to the pathogenesis of type 2 diabetes, the pancreas is the least studied organ due to its inaccessible anatomical position. Previous ultrasound and CT studies have suggested a possible decrease in pancreatic volume in type 2 diabetes. However, ultrasound techniques are relatively insensitive while CT uses ionizing radiation, making these modalities unsuitable for precise, longitudinal studies designed to explore the underlying mechanisms of type 2 diabetes. Hence there is a need to develop a non-invasive, safe and precise method to quantitate pancreas volume.
We developed and applied magnetic resonance imaging at 3.0T to obtain balanced turbo field echo (BTFE) structural images of the pancreas, together with 3-point Dixon images to quantify pancreatic triglyceride content. Pancreas volume, morphology and triglyceride content was quantified in a group of 41 subjects with well-controlled type 2 diabetes (HbA1c ≤ 7.6%) taking only metformin (duration of T2DM 5.7 ± 0.7 years), and a control group of 14 normal glucose tolerance subjects matched for age, weight and sex.
The mean pancreatic volume was found to be 33% less in type 2 diabetes than in normal glucose tolerant subjects (55.5 ± 2.8 vs. 82.6 ± 4.8 cm3; p < 0.0001). Pancreas volume was positively correlated with HOMA-β in the type 2 diabetes subjects (r = 0.31; p = 0.03) and controls (r = 0.46; p = 0.05) considered separately; and in the whole population studied (r = 0.37; p = 0.003). In type 2 diabetes, the pancreas was typically involuted with a serrated border. Pancreatic triglyceride content was 23% greater (5.4 ± 0.3 vs. 4.4 ± 0.4%; p = 0.02) in the type 2 diabetes group.
This study describes for the first time gross abnormalities of the pancreas in early type 2 diabetes and quantifies the decrease in pancreas size, the irregular morphology and increase in fat content.
Although lifestyle changes encompassing weight loss and exercise remain the cornerstone of non-alcoholic fatty liver disease (NAFLD) management, the effect of different types of exercise on NAFLD is ...unknown. This study defines the effect of modified high-intensity interval training (HIIT) on liver fat, cardiac function and metabolic control in adults with NAFLD. Twenty-three patients with NAFLD age 54±10 years, body mass index (BMI) 31±4 kg/m(2), intra-hepatic lipid >5%) were assigned to either 12 weeks HIIT or standard care (controls). HIIT involved thrice weekly cycle ergometry for 30-40 min. MRI and spectroscopy were used to assess liver fat, abdominal fat and cardiac structure/function/energetics. Glucose control was assessed by oral glucose tolerance test and body composition by air displacement plethysmography. Relative to control, HIIT decreased liver fat (11±5% to 8±2% compared with 10±4% to 10±4% P=0.019), whole-body fat mass (35±7 kg to 33±8 kg compared with 31±9 kg to 32±9 kg, P=0.013), alanine (52±29 units/l to 42±20 units/l compared with 47±22 units/l to 51±24 units/l, P=0.016) and aspartate aminotransferase (AST; 36±18 units/l to 33±15 units/l compared with 31±8 units/l to 35±8 units/l, P=0.017) and increased early diastolic filling rate (244±84 ml/s to 302±107 ml/s compared with 255±82 ml/s to 251±82 ml/s, P=0.018). There were no between groups differences in glucose control. Modified HIIT reduces liver fat and improves body composition alongside benefits to cardiac function in patients with NAFLD and should be considered as part of the broader treatment regimen by clinical care teams. ISRCTN trial ID: ISRCTN78698481.
The muscular dystrophies are rare orphan diseases, characterized by progressive muscle weakness: the most common and well known is Duchenne muscular dystrophy which affects young boys and progresses ...quickly during childhood. However, over 70 distinct variants have been identified to date, with different rates of progression, implications for morbidity, mortality, and quality of life. There are presently no curative therapies for these diseases, but a range of potential therapies are presently reaching the stage of multi-centre, multi-national first-in-man clinical trials. There is a need for sensitive, objective end-points to assess the efficacy of the proposed therapies. Present clinical measurements are often too dependent on patient effort or motivation, and lack sensitivity to small changes, or are invasive. Quantitative MRI to measure the fat replacement of skeletal muscle by either chemical shift imaging methods (Dixon or IDEAL) or spectroscopy has been demonstrated to provide such a sensitive, objective end-point in a number of studies. This review considers the importance of the outcome measures, discusses the considerations required to make robust measurements and appropriate quality assurance measures, and draws together the existing literature for cross-sectional and longitudinal cohort studies using these methods in muscular dystrophy.
Objective:
Suboptimal mitochondrial function has been implicated in several disorders in which fatigue is a prominent feature. Vitamin D deficiency is a well-recognized cause of fatigue and myopathy. ...The aim of this study was to examine the effects of cholecalciferol therapy on skeletal mitochondrial oxidative function in symptomatic, vitamin D-deficient individuals.
Design:
This longitudinal study assessed mitochondrial oxidative phosphorylation in the gastrosoleus compartment using phosphorus-31 magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics in 12 symptomatic, severely vitamin D-deficient subjects before and after treatment with cholecalciferol. All subjects had serum assays before and after cholecalciferol therapy to document serum 25-hydroxyvitamin D (25OHD) and bone profiles. Fifteen healthy controls also underwent 31P-magnetic resonance spectroscopy and serum 25OHD assessment.
Results:
The phosphocreatine recovery half-time (τ1/2PCr) was significantly reduced after cholecalciferol therapy in the subjects indicating an improvement in maximal oxidative phosphorylation (34.44 ± 8.18 sec to 27.84 ± 9.54 sec, P < .001). This was associated with an improvement in mean serum 25OHD levels (8.8 ± 4.2 nmol/L to 113.8 ± 51.5 nmol/L, P < .001). There was no difference in phosphate metabolites at rest. A linear regression model showed that decreasing serum 25OHD levels was associated with increasing τ1/2PCr (r = −0.41, P = .009). All patients reported an improvement in fatigue after cholecalciferol therapy.
Conclusions:
Cholecalciferol therapy augments muscle mitochondrial maximal oxidative phosphorylation after exercise in symptomatic, vitamin D-deficient individuals. This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could at least be partly responsible for the fatigue experienced by these patients. For the first time, we demonstrate a link between vitamin D and the mitochondria in human skeletal muscle.
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 type 2 diabetes is associated with a major fall in liver fat export•Re-emergence is associated with increased liver-derived plasma triglycerides•These changes are reflected by intra-pancreatic fat content•Beta-cell dysfunction is related to raised intra-pancreatic fat
Al Mrabeh et al. show that remission of type 2 diabetes over 2 years is associated with decreased liver triglyceride export and intra-pancreatic fat. Weight gain and re-emergence of diabetes were associated with increase in liver-derived plasma triglyceride, re-accumulation of fat within the pancreas, and recurrence of beta cell dysfunction.
This study determined whether the decrease in pancreatic triacylglycerol during weight loss in type 2 diabetes mellitus (T2DM) is simply reflective of whole-body fat or specific to diabetes and ...associated with the simultaneous recovery of insulin secretory function.
Individuals listed for gastric bypass surgery who had T2DM or normal glucose tolerance (NGT) matched for age, weight, and sex were studied before and 8 weeks after surgery. Pancreas and liver triacylglycerol were quantified using in-phase, out-of-phase MRI. Also measured were the first-phase insulin response to a stepped intravenous glucose infusion, hepatic insulin sensitivity, and glycemic and incretin responses to a semisolid test meal.
Weight loss after surgery was similar (NGT: 12.8 ± 0.8% and T2DM: 13.6 ± 0.7%) as was the change in fat mass (56.7 ± 3.3 to 45.4 ± 2.3 vs. 56.6 ± 2.4 to 43.0 ± 2.4 kg). Pancreatic triacylglycerol did not change in NGT (5.1 ± 0.2 to 5.5 ± 0.4%) but decreased in the group with T2DM (6.6 ± 0.5 to 5.4 ± 0.4%; P = 0.007). First-phase insulin response to a stepped intravenous glucose infusion did not change in NGT (0.24 0.13-0.46 to 0.23 0.19-0.37 nmol ⋅ min(-1) ⋅ m(-2)) but normalized in T2DM (0.08 -0.01 to -0.10 to 0.22 0.07-0.30) nmol ⋅ min(-1) ⋅ m(-2) at week 8 (P = 0.005). No differential effect of incretin secretion was observed after gastric bypass, with more rapid glucose absorption bringing about equivalently enhanced glucagon-like peptide 1 secretion in the two groups.
The fall in intrapancreatic triacylglycerol in T2DM, which occurs during weight loss, is associated with the condition itself rather than decreased total body fat.
Aims/hypothesis
Cardiac disease remains the leading cause of mortality in type 2 diabetes, yet few strategies to target cardiac dysfunction have been developed. This randomised controlled trial aimed ...to investigate high intensity intermittent training (HIIT) as a potential therapy to improve cardiac structure and function in type 2 diabetes. The impact of HIIT on liver fat and metabolic control was also investigated.
Methods
Using an online random allocation sequence, 28 patients with type 2 diabetes (metformin and diet controlled) were randomised to 12 weeks of HIIT (
n
= 14) or standard care (
n
= 14). Cardiac structure and function were measured by 3.0 T MRI and tagging. Liver fat was determined by
1
H-magnetic resonance spectroscopy and glucose control by an OGTT. MRI analysis was performed by an observer blinded to group allocation. All study procedures took place in Newcastle upon Tyne, UK.
Results
Five patients did not complete the study and were therefore excluded from analysis: this left 12 HIIT and 11 control patients for the intention-to-treat analysis. Compared with controls, HIIT improved cardiac structure (left ventricular wall mass 104 ± 17 g to 116 ± 20 g vs 107 ± 25 g to 105 ± 25 g,
p <
0.05) and systolic function (stroke volume 76 ± 16 ml to 87 ± 19 ml vs 79 ± 14 ml to 75 ± 15 ml,
p <
0.01). Early diastolic filling rates increased (241 ± 84 ml/s to 299 ± 89 ml/s vs 250 ± 44 ml/s to 251 ± 47 ml/s,
p <
0.05) and peak torsion decreased (8.1 ± 1.8° to 6.9 ± 1.6° vs 7.1 ± 2.2° to 7.6 ± 1.9°,
p <
0.05) in the treatment group. Following HIIT, there was a 39% relative reduction in liver fat (
p <
0.05) and a reduction in HbA
1c
(7.1 ± 1.0% 54.5 mmol/mol to 6.8 ± 0.9% 51.3 mmol/mol vs 7.2 ± 0.5% 54.9 mmol/mol to 7.4 ± 0.7% 57.0 mmol/mol,
p <
0.05). Changes in liver fat correlated with changes in HbA
1c
(
r =
0.70,
p <
0.000) and 2 h glucose (
r =
0.57,
p <
0.004). No adverse events were recorded.
Conclusions/interpretation
This is the first study to demonstrate improvements in cardiac structure and function, along with the greatest reduction in liver fat, to be recorded following an exercise intervention in type 2 diabetes. HIIT should be considered by clinical care teams as a therapy to improve cardiometabolic risk in patients with type 2 diabetes.
Trial registration:
www.isrctn.com
78698481
Funding:
Medical Research Council.
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 0.110.0005–0.51 nmol/min/m2, p < 0.0001) defined those who returned to non-diabetic glucose control and this was durable at 12 months (0.110.005–0.81 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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•Substantial weight loss can reverse the processes underlying type 2 diabetes•Liver fat content is normalized and pancreas fat content decreased in all•Return to non-diabetic glucose control depends upon β cell ability to recover
Type 2 diabetes has long been regarded as lifelong and progressive. Taylor et al. demonstrate that weight loss of over 10 kg results in normalization of ectopic fat within liver and pancreas. This is associated with durable recovery of β cell function and non-diabetic glucose control in the majority.
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