Sarah Steven

Very-Low-Calorie Diet and 6 Months of Weight Stability in Type 2 Diabetes: Pathophysiological Changes in Responders and Nonresponders

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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. CONCLUSIONS 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.

Weight Loss Decreases Excess Pancreatic Triacylglycerol Specifically in Type 2 Diabetes

OBJECTIVE 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. RESEARCH DESIGN AND METHODS 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. RESULTS 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. CONCLUSIONS The fall in intrapancreatic triacylglycerol in T2DM, which occurs during weight loss, is associated with the condition itself rather than decreased total body fat.

Restoring normoglycaemia by use of a very low calorie diet in long- and short-duration Type 2 diabetes

To establish whether an 8‐week very‐low‐calorie diet could improve glycaemic control in Type 2 diabetes of long duration.

Population response to information on reversibility of Type 2 diabetes.

Following publication of the Counterpoint Study (on the reversibility of Type 2 diabetes using a very low energy diet), the extent of public interest prompted the authors to make available, on a website, general information about reversing diabetes. Shortly thereafter, individuals began to feed back their personal experiences of attempting to reverse their diabetes. We have collated this information on the effects of energy restriction in motivated individuals with Type 2 diabetes that has been achieved outside a research setting.

Reversal of Type 2 diabetes after bariatric surgery is determined by the degree of achieved weight loss in both short‐ and long‐duration diabetes

To define the impact of duration of diabetes and extent of weight loss on the reversibility of Type 2 diabetes after bariatric surgery.

Calorie restriction and not glucagon‐like peptide‐1 explains the acute improvement in glucose control after gastric bypass in Type 2 diabetes

To compare directly the impact of glucagon‐like peptide‐1 secretion on glucose metabolism in individuals with Type 2 diabetes listed for Roux‐en‐Y gastric bypass surgery, randomized to be studied before and 7 days after undergoing Roux‐en‐Y gastric bypass or after following a very‐low‐calorie diet.

Acceptability of a very‐low‐energy diet in Type 2 diabetes: patient experiences and behaviour regulation

To evaluate the acceptability of an 8‐week very‐low‐energy diet for remission of Type 2 diabetes, and to identify barriers and facilitators of adherence and behaviour‐regulation strategies used by participants in the Counterbalance study.

Pancreatic triacylglycerol distribution in type 2 diabetes

To the Editor: The paper by Begovatz and colleagues concluded that there was no fat in the parenchymal tissue of the pancreas, and hence local release of fatty acids could not influence endocrine function [1]. The authors describe intralobular fat within the pancreas as detected by spectroscopy but then concluded that there was no fat in the parenchyma of the pancreas. This conclusion relied upon magnetic resonance (MR) techniques. We draw attention to three serious errors in the MR methodology employed, and to the sound evidence for the existence of parenchymal fat. First, the imaging method used to measure parenchymal fat yielded negative percentages for pancreas parenchymal fat in approximately half of all individuals, the range of individual parenchymal fat appearing to be from −3% to +4%. Negative fat content of tissue is a concept of no biological validity. The lower limit of detection is stated by the authors as 2%, and from Fig. 2l in their paper it can be seen that this means the majority of their observations cannot yield what they themselves define as a meaningful result. There appears to be a problem of calibration at low fat fraction, possibly caused by the noise performance of fitting too many variables to a twopoint Dixon acquisition, rather than using three or more echoes. Although the authors claim that the technique used has been validated, their supporting reference 29 is an abstract that relates to the simpler matter of measuring liver fat content. Second, it is suggested that there is no fat in the parenchyma of the pancreas but that fat within the pancreas in type 2 diabetes is contained in thick bands of adipose tissue. We have thoroughly assessed over 100 pancreases of people with diabetes and 32 with normal glucose tolerance using our published three-point Dixon method [2]. As illustrated by six examples in our Fig. 1, fat is distributed at a low level throughout each pancreas, and localised very high concentrations of fat are rare within the organ. One of the advantages of the three-point Dixon technique is that it is possible to study smaller organs with precise knowledge of boundaries [3]. We have previously reported that the pancreas is 30% smaller in volume and has a more serrated border in type 2 diabetes compared with age-, weightand sex-matched controls [4]. Care is indeed required in selecting regions of interest in which to quantify triacylglycerol in the parenchyma of the pancreas and this underscores the value of using an imagingbased method. Third, the authors state that they wanted to assess fat distribution in the pancreas in three supposedly different regions [1]. To do this they employed two very different methods, modified Dixon imaging and spectroscopy. This introduces differences related to the methods. Yet the assessment would more simply be carried out by use of a properly established three-point Dixon technique. Using this method, the region of * Roy Taylor roy.taylor@ncl.ac.uk

Dietary reversal of Type 2 diabetes motivated by research knowledge

and the appropriate rise in insulin and C-peptide suggest that a subtle abnormality in insulin sensitivity may account for the lack ofglucoseclearanceduring intenseexercise. Perhaps if the subject was unfit and overweight, diabetes would be unmasked. Is any form of treatment indicated? As the subject had a normal oral glucose tolerance test, one could argue that treatment is not required. However, if the abnormality is related to excess hepatic glucose output with subtle insulin resistance, then an ideal therapeutic option would bemetformin, whichmight prevent the future development of diabetes [10]. However, blood lactate levels increased approximately threefold during intense exercise, which would not be the ideal environment for therapy with metformin, which is associated with lactic acidosis [11].

Quantification of intrapancreatic fat in type 2 diabetes by MRI

Objectives 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. Methods 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. Results 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. Conclusion 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.