Sex differences in intraorgan fat levels and hepatic lipid metabolism: implications for cardiovascular health and remission of type 2 diabetes after dietary weight loss.

AIMS/HYPOTHESIS: Type 2 diabetes confers a greater relative increase in CVD risk in women compared with men. We examined sex differences in intraorgan fat and hepatic VLDL1-triacylglycerol (VLDL1-TG) export before and after major dietary weight loss. METHODS: A group with type 2 diabetes (n = 64, 30 male/34 female) and a group of healthy individuals (n = 25, 13 male/12 female) were studied. Intraorgan and visceral fat were quantified by magnetic resonance and VLDL1-TG export by intralipid infusion techniques. RESULTS: Triacylglycerol content of the liver and pancreas was elevated in people with diabetes with no sex differences (liver 16.4% [9.3-25.0%] in women vs 11.9% [7.0-23.1%] in men, p = 0.57, and pancreas 8.3 ± 0.5% vs 8.5 ± 0.4%, p = 0.83, respectively). In the absence of diabetes, fat levels in both organs were lower in women than men (1.0% [0.9-1.7%] vs 4.5% [1.9-8.0%], p = 0.005, and 4.7 ± 0.4% vs 7.6 ± 0.5%, p< 0.0001, respectively). Women with diabetes had higher hepatic VLDL1-TG production rate and plasma VLDL1-TG than healthy women (559.3 ± 32.9 vs 403.2 ± 45.7 mg kg-1 day-1, p = 0.01, and 0.45 [0.26-0.77] vs 0.25 [0.13-0.33] mmol/l, p = 0.02), whereas there were no differences in men (548.8 ± 39.8 vs 506.7 ± 29.2 mg kg-1 day-1, p = 0.34, and 0.72 [0.53-1.15] vs 0.50 [0.32-0.68] mmol/l, p = 0.26). Weight loss decreased intraorgan fat and VLDL1-TG production rates regardless of sex, and these changes were accompanied by similar rates of diabetes remission (65.4% vs 71.0%) and CVD risk reduction (59.8% vs 41.5%) in women and men, respectively. CONCLUSIONS/INTERPRETATION: In type 2 diabetes, women have liver and pancreas fat levels as high as those of men, associated with raised hepatic VLDL1-TG production rates. Dynamics of triacylglycerol turnover differ between sexes in type 2 diabetes and following weight loss. These changes may contribute to the disproportionately raised cardiovascular risk of women with diabetes.

Weight loss-induced increase in fasting ghrelin concentration is a predictor of weight regain: Evidence from the Diabetes Remission Clinical Trial (DiRECT).

AIM: To investigate whether appetite-related hormones were predictors of weight regain in the Diabetes Remission Clinical Trial (DiRECT). MATERIALS AND METHODS: DiRECT is a cluster-randomized clinical trial, designed to assess the effect of weight loss on type 2 diabetes remission. For this post hoc analysis, data were available for 253 (147 interventions, 106 controls) individuals with type 2 diabetes (age 53.6 ± 7.5 years, body mass index 34.7 ± 4.4 kg/m2 , 59% men). Intervention participants received a 24-month weight management programme, and controls remained on usual diabetes care. Fasting plasma concentrations of leptin, ghrelin, glucagon-like peptide-1 and peptide YY were measured at baseline, 12 months and 24 months in all participants, and at 5 months in a subset of participants in the intervention (n = 56) and control groups (n = 22). Potential predictors were examined using multivariable linear regression models. RESULTS: The intervention group lost 14.3 ± 6.0% body weight at 5 months but regained weight over time, with weight losses of 10.0 ± 7.5% at 12 months and 7.6 ± 6.3% at 24 months. Weight loss in controls was 1.1 ± 3.7% and 2.1 ± 5.0% at 12 and 24 months, respectively. Body weight increased by 2.3% (95% confidence interval [CI] 0.4, 4.1; P = 0.019) between 12 and 24 months for every 1-ng/mL increase in ghrelin between baseline and 12 months, and weight regain between 12 and 24 months was increased by 1.1% (95% CI 0.2, 2.0; P = 0.023) body weight for every 1-ng/mL increase in ghrelin at 12 months. CONCLUSION: The rise in ghrelin (but not any other measured hormone) during diet-induced weight loss was a predictor of weight regain during follow-up, and concentrations remained elevated over time, suggesting a small but significant compensatory drive to regain weight. Attenuating the effects of ghrelin may improve weight-loss maintenance.

Weight loss induced increase in fasting ghrelin concentration is a predictor of weight regain: evidence from the Diabetes Remission Clinical Trial.

AIM: To investigate whether appetite-related hormones were predictors of weight regain in the Diabetes Remission Clinical Trial (DiRECT). MATERIALS AND METHODS: DiRECT is a cluster-randomised clinical trial designed to assess the effect of weight-loss on type 2 diabetes remission. For this post hoc analysis, data were available for 253 (147 interventions, 106 controls) individuals with type 2 diabetes (aged 53.6±7.5 years, BMI 34.7±4.4 kg/m2, 59% males). Intervention participants received a 24-month weight-management programme and controls remained on usual diabetes care. Fasting plasma concentrations of leptin, ghrelin, GLP-1, and PYY were measured at baseline, 12 and 24-months in all participants, and at 5-months in a subset of interventions (n=56) and controls (n=22). Potential predictors were examined using multivariable linear regression models. RESULTS: The intervention group lost 14.3±6.0% body-weight at 5-months but regained over time, with weight-losses of 10.0±7.5% at 12-months and 7.6±6.3% at 24-months. Weight-loss in controls was 1.1±3.7% and 2.1±5.0% at 12 and 24-months, respectively. Body-weight increased by 2.3% [95% CI: 0.4,4.1]; p=0.019) between 12 and 24-months for every 1 ng/ml increase in ghrelin between baseline and 12-months, and weight regain between 12 and 24-months was increased by 1.1% (95% CI: 0.2,2.0; p=0.023) body-weight for every 1 ng/ml increase in ghrelin at 12-months. CONCLUSION: The rise in ghrelin (but not any other measured hormone) during diet-induced weight-loss was a predictor of weight regain during follow-up, and concentrations remained elevated over time, suggesting a small but significant compensatory drive to regain weight. Attenuating the effects of ghrelin may improve WLM. This article is protected by copyright. All rights reserved.

Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial.

BACKGROUND: Type 2 diabetes is a chronic disorder that requires lifelong treatment. We aimed to assess whether intensive weight management within routine primary care would achieve remission of type 2 diabetes. METHODS: We did this open-label, cluster-randomised trial (DiRECT) at 49 primary care practices in Scotland and the Tyneside region of England. Practices were randomly assigned (1:1), via a computer-generated list, to provide either a weight management programme (intervention) or best-practice care by guidelines (control), with stratification for study site (Tyneside or Scotland) and practice list size (>5700 or ≤5700). Participants, carers, and research assistants who collected outcome data were aware of group allocation; however, allocation was concealed from the study statistician. We recruited individuals aged 20-65 years who had been diagnosed with type 2 diabetes within the past 6 years, had a body-mass index of 27-45 kg/m2, and were not receiving insulin. The intervention comprised withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825-853 kcal/day formula diet for 3-5 months), stepped food reintroduction (2-8 weeks), and structured support for long-term weight loss maintenance. Co-primary outcomes were weight loss of 15 kg or more, and remission of diabetes, defined as glycated haemoglobin (HbA1c) of less than 6·5% (<48 mmol/mol) after at least 2 months off all antidiabetic medications, from baseline to 12 months. These outcomes were analysed hierarchically. This trial is registered with the ISRCTN registry, number 03267836. FINDINGS: Between July 25, 2014, and Aug 5, 2017, we recruited 306 individuals from 49 intervention (n=23) and control (n=26) general practices; 149 participants per group comprised the intention-to-treat population. At 12 months, we recorded weight loss of 15 kg or more in 36 (24%) participants in the intervention group and no participants in the control group (p<0·0001). Diabetes remission was achieved in 68 (46%) participants in the intervention group and six (4%) participants in the control group (odds ratio 19·7, 95% CI 7·8-49·8; p<0·0001). Remission varied with weight loss in the whole study population, with achievement in none of 76 participants who gained weight, six (7%) of 89 participants who maintained 0-5 kg weight loss, 19 (34%) of 56 participants with 5-10 kg loss, 16 (57%) of 28 participants with 10-15 kg loss, and 31 (86%) of 36 participants who lost 15 kg or more. Mean bodyweight fell by 10·0 kg (SD 8·0) in the intervention group and 1·0 kg (3·7) in the control group (adjusted difference -8·8 kg, 95% CI -10·3 to -7·3; p<0·0001). Quality of life, as measured by the EuroQol 5 Dimensions visual analogue scale, improved by 7·2 points (SD 21·3) in the intervention group, and decreased by 2·9 points (15·5) in the control group (adjusted difference 6·4 points, 95% CI 2·5-10·3; p=0·0012). Nine serious adverse events were reported by seven (4%) of 157 participants in the intervention group and two were reported by two (1%) participants in the control group. Two serious adverse events (biliary colic and abdominal pain), occurring in the same participant, were deemed potentially related to the intervention. No serious adverse events led to withdrawal from the study. INTERPRETATION: Our findings show that, at 12 months, almost half of participants achieved remission to a non-diabetic state and off antidiabetic drugs. Remission of type 2 diabetes is a practical target for primary care. FUNDING: Diabetes UK.

Clinical and metabolic features of the randomised controlled Diabetes Remission Clinical Trial (DiRECT) cohort.

AIMS/HYPOTHESIS: Substantial weight loss in type 2 diabetes can achieve a return to non-diabetic biochemical status, without the need for medication. The Diabetes Remission Clinical Trial (DiRECT), a cluster-randomised controlled trial, is testing a structured intervention designed to achieve and sustain this over 2 years in a primary care setting to determine practicability for routine clinical practice. This paper reports the characteristics of the baseline cohort. METHODS: People with type 2 diabetes for <6 years with a BMI of 27-45 kg/m2 were recruited in 49 UK primary care practices, randomised to either best-practice diabetes care alone or with an additional evidence-based weight management programme (Counterweight-Plus). The co-primary outcomes, at 12 months, are weight loss ≥15 kg and diabetes remission (HbA1c <48 mmol/mol [6.5%]) without glucose-lowering therapy for at least 2 months. Outcome assessors are blinded to group assignment. RESULTS: Of 1510 people invited, 423 (28%) accepted; of whom, 306 (72%) were eligible at screening and gave informed consent. Seven participants were later found to have been randomised in error and one withdrew consent, leaving 298 (176 men, 122 women) who will form the intention to treat (ITT) population for analysis. Mean (SD) age was 54.4 (7.6) years, duration of diabetes 3.0 (1.7) years, BMI 34.6 (4.4) kg/m2 for all participants (34.2 (4.2) kg/m2 in men and 35.3 (4.6) kg/m2 in women) and baseline HbA1c (on treatment) 59.3 (12.7) mmol/mol (7.6% [1.2%]). The recruitment rate in the intervention and control groups, and comparisons between the subgroups recruited in Scotland and England, showed few differences. CONCLUSIONS/INTERPRETATION: DiRECT has recruited a cohort of people with type 2 diabetes with characteristics similar to those seen in routine practice, indicating potential widespread applicability. Over 25% of the eligible population wished to participate in the study, including a high proportion of men, in line with the prevalence distribution of type 2 diabetes. TRIAL REGISTRATION: www.controlled-trials.com/ISRCTN03267836 ; date of registration 20 December 2013.

Morphology of the pancreas in type 2 diabetes: effect of weight loss with or without normalisation of insulin secretory capacity.

AIMS/HYPOTHESIS: This study was designed to establish whether the low volume and irregular border of the pancreas in type 2 diabetes would be normalised after reversal of diabetes. METHODS: A total of 29 individuals with type 2 diabetes undertook a very low energy (very low calorie) diet for 8 weeks followed by weight maintenance for 6 months. Methods were established to quantify the pancreas volume and degree of irregularity of the pancreas border. Three-dimensional volume-rendering and fractal dimension (FD) analysis of the MRI-acquired images were employed, as was three-point Dixon imaging to quantify the fat content. RESULTS: There was no change in pancreas volume 6 months after reversal of diabetes compared with baseline (52.0 ± 4.9 cm(3) and 51.4 ± 4.5 cm(3), respectively; p = 0.69), nor was any volumetric change observed in the non-responders. There was an inverse relationship between the volume and fat content of the pancreas in the total study population (r =-0.50, p = 0.006). Reversal of diabetes was associated with an increase in irregularity of the pancreas borders between baseline and 8 weeks (FD 1.143 ± 0.013 and 1.169 ± 0.006, respectively; p = 0.05), followed by a decrease at 6 months (1.130 ± 0.012, p = 0.006). On the other hand, no changes in FD were seen in the non-reversed group. CONCLUSIONS/INTERPRETATION: Restoration of normal insulin secretion did not increase the subnormal pancreas volume over 6 months in the study population. A significant change in irregularity of the pancreas borders occurred after acute weight loss only after reversal of diabetes. Pancreas morphology in type 2 diabetes may be prognostically important, and its relationship to change in beta cell function requires further study.

ß-Cell Dysfunction, Hepatic Lipid Metabolism, and Cardiovascular Health in Type 2 Diabetes: New Directions of Research and Novel Therapeutic Strategies.

Cardiovascular disease (CVD) remains a major problem for people with type 2 diabetes mellitus (T2DM), and dyslipidemia is one of the main drivers for both metabolic diseases. In this review, the major pathophysiological and molecular mechanisms of ß-cell dysfunction and recovery in T2DM are discussed in the context of abnormal hepatic lipid metabolism and cardiovascular health. (i) In normal health, continuous exposure of the pancreas to nutrient stimulus increases the demand on ß-cells. In the long term, this will not only stress ß-cells and decrease their insulin secretory capacity, but also will blunt the cellular response to insulin. (ii) At the pre-diabetes stage, ß-cells compensate for insulin resistance through hypersecretion of insulin. This increases the metabolic burden on the stressed ß-cells and changes hepatic lipoprotein metabolism and adipose tissue function. (iii) If this lipotoxic hyperinsulinemic environment is not removed, ß-cells start to lose function, and CVD risk rises due to lower lipoprotein clearance. (iv) Once developed, T2DM can be reversed by weight loss, a process described recently as remission. However, the precise mechanism(s) by which calorie restriction causes normalization of lipoprotein metabolism and restores ß-cell function are not fully established. Understanding the pathophysiological and molecular basis of ß-cell failure and recovery during remission is critical to reduce ß-cell burden and loss of function. The aim of this review is to highlight the link between lipoprotein export and lipid-driven ß-cell dysfunction in T2DM and how this is related to cardiovascular health. A second aim is to understand the mechanisms of ß-cell recovery after weight loss, and to explore new areas of research for developing more targeted future therapies to prevent T2DM and the associated CVD events.

Effect of Weight Loss by Low-Calorie Diet on Cardiovascular Health in Type 2 Diabetes: An Interventional Cohort Study.

Cardiovascular disease (CVD) remains a major problem for people with type 2 diabetes (T2DM), and the leading cause of death worldwide. We aimed to determine cardiovascular benefits of weight loss with or without remission of diabetes, and to assess utility of plasma biomarkers. 29 people with T2DM were studied at baseline and after dietary weight loss. Change in plasma adipokines and lipid related markers was examined in relation to weight loss, diabetes remission, 10-year cardiovascular risk (QRISK), and duration of diabetes. QRISK decreased markedly after weight loss (18.9 ± 2.2 to 11.2 ± 1.6%, p < 0.0001) in both responders and non-responders, but non-responders remained at higher risk (15.0 ± 2.0 vs. 5.8 ± 1.6%, p < 0.0001). At baseline, plasma GDF-15 was higher in longer diabetes duration (1.19 ± 0.14 vs. 0.82 ± 0.09 ng/mL, p = 0.034), as was the QRISK (22.8 ± 2.6 vs. 15.3 ± 3.4%, p = 0.031). Leptin, GDF-15 and FGF-21 decreased whereases adiponectin increased after weight loss in responders and non-responders. However, the level of FGF-21 remained higher in non-responders (0.58 [0.28-0.71] vs. 0.25 [0.15-0.42] ng/mL, p = 0.007). QRISK change correlated with change in plasma VLDL1-TG (r = 0.489, p = 0.007). There was a positive correlation between rise in HDL cholesterol and the decrease in leptin (r = 0.57, p = 0.001), or rise in adiponectin (r = 0.58, p = 0.001) levels. In conclusion, weight loss markedly decreases cardiometabolic risk particularly when remission of diabetes is achieved. Leptin, adiponectin, GDF-15 and FGF-21 changes were related to weight loss not remission of diabetes. Normalization of 10-year cardiovascular risk and heart age is possible after substantial dietary weight loss and remission of T2DM.

Measurement of intraorgan fat and hepatic output of triglycerides in human type 2 diabetes by magnetic resonance and intralipid infusion techniques.

Liver fat content and the linked rate of export of triglyceride are central to the etiology of type 2 diabetes, as well as to the cardiovascular effects of fatty liver disease. Measurement in humans of intrahepatic and intrapancreatic fat content is described using magnetic resonance techniques and quantification of the rate of hepatic secretion of very low density lipoprotein using a non-isotopic competitive blocking of tissue uptake. This protocol is non-invasive, can be repeated sequentially, and does not involve ionizing radiation. For complete details on the use and execution of this protocol, please refer to (Taylor et al., 2018) and (Al-Mrabeh et al., 2020b).

Pathogenesis and remission of type 2 diabetes: what has the twin cycle hypothesis taught us?

Type 2 diabetes has been regarded a complex multifactorial disease that lead to serious health complications including high cardiovascular risks. The twin cycle hypothesis postulated that both hepatic insulin resistance and dysfunction rather than death of beta (ß) cell determine diabetes onset. Several studies were carried out to test this hypothesis, and all demonstrated that chronic excess calorie intake and ectopic fat accumulation within the liver and pancreas are fundamental to the development of this disease. However, these recent research advances cannot determine the exact cause of this disease. In this review, the major factors that contribute to the pathogenesis and remission of type 2 diabetes will be outlined. Importantly, the effect of disordered lipid metabolism, characterized by altered hepatic triglyceride export will be discussed. Additionally, the observed changes in pancreas morphology in type 2 diabetes will be highlighted and discussed in relation to ß cell function.

2-year remission of type 2 diabetes and pancreas morphology: a post-hoc analysis of the DiRECT open-label, cluster-randomised trial.

BACKGROUND: The pancreas is small and irregular in shape in people with type 2 diabetes. If these abnormalities are caused by the disease state itself rather than being a predisposing factor, remission of type 2 diabetes should restore normal pancreas morphology. The objective of this study was to determine whether changes in pancreas volume and shape occurred during 2 years of remission. METHODS: For this post-hoc analysis, we included a subset of adult participants of the Diabetes Remission Clinical Trial (DiRECT), who had type 2 diabetes and were randomly assigned to a weight management intervention or routine diabetes management. Intervention group participants were categorised as responders (HbA1c <6·5% [48 mmol/mol] and fasting blood glucose <7·0 mmol/L, off all anti-diabetes medication) and non-responders, who were classified as remaining diabetic. Data on pancreas volume and irregularity of pancreas border at baseline, 5 months, 12 months, and 24 months after intervention were compared between responders and non-responders; additional comparisons were made between control group participants with type 2 diabetes and a non-diabetic comparator (NDC) group, who were matched to the intervention group by age, sex, and post-weight-loss weight, to determine the extent of any normalisation. We used a mixed-effects regression model based on repeated measures ANOVA with correction for potential confounding. Magnetic resonance techniques were employed to quantify pancreas volume, the irregularity of the pancreas borders, and intrapancreatic fat content. ß-cell function and biomarkers of tissue growth were also measured. FINDINGS: Between July 25, 2015, and Aug 5, 2016, 90 participants with type 2 diabetes in the DiRECT subset were randomly assigned to intervention (n=64) or control (n=26) and were assessed at baseline; a further 25 non-diabetic participants were enrolled into the NDC group. At baseline, mean pancreas volume was 61·7 cm3 (SD 16·0) in all participants with type 2 diabetes and 79·8 cm3 (14·3) in the NDC group (p<0·0001). At 24 months, pancreas volume had increased by 9·4 cm3 (95% CI 6·1 to 12·8) in responders compared with 6·4 cm3 (2·5 to 10·3) in non-responders (p=0·0008). Pancreas borders at baseline were more irregular in participants with type 2 diabetes than in the NDC group (fractal dimension 1·138 [SD 0·027] vs 1·097 [0·025]; p<0·0001) and had normalised by 24 months in responders only (1·099 [0·028]). Intrapancreatic fat declined by 1·02 percentage points (95% CI 0·53 to 1·51) in 32 responders and 0·51% (-0·17 to 1·19) in 13 non-responders (p=0·23). INTERPRETATION: These data show for the first time, to our knowledge, reversibility of the abnormal pancreas morphology of type 2 diabetes by weight loss-induced remission. FUNDING: Diabetes UK.

Time Course of Normalization of Functional ß-Cell Capacity in the Diabetes Remission Clinical Trial After Weight Loss in Type 2 Diabetes.

OBJECTIVE: To assess functional ß-cell capacity in type 2 diabetes during 2 years of remission induced by dietary weight loss. RESEARCH DESIGN AND METHODS: A Stepped Insulin Secretion Test with Arginine was used to quantify functional ß-cell capacity by hyperglycemia and arginine stimulation. Thirty-nine of 57 participants initially achieved remission (HbA1c <6.5% [<48 mmol/mol] and fasting plasma glucose <7 mmol/L on no antidiabetic drug therapy) with a 16.4 ± 7.7 kg weight loss and were followed up with supportive advice on avoidance of weight regain. At 2 years, 20 participants remained in remission in the study. A nondiabetic control (NDC) group, matched for age, sex, and weight after weight loss with the intervention group, was studied once. RESULTS: During remission, median (interquartile range) maximal rate of insulin secretion increased from 581 (480-811) pmol/min/m2 at baseline to 736 (542-998) pmol/min/m2 at 5 months, 942 (565-1,240) pmol/min/m2 at 12 months (P = 0.028 from baseline), and 936 (635-1,435) pmol/min/m2 at 24 months (P = 0.023 from baseline; n = 20 of 39 of those initially in remission). This was comparable to the NDC group (1,016 [857-1,507] pmol/min/m2) by 12 (P = 0.064) and 24 (P = 0.244) months. Median first-phase insulin response increased from baseline to 5 months (42 [4-67] to 107 [59-163] pmol/min/m2; P < 0.0001) and then remained stable at 12 and 24 months (110 [59-201] and 125 [65-166] pmol/min/m2, respectively; P < 0.0001 vs. baseline) but lower than that of the NDC group (250 [226-429] pmol/min/m2; P < 0.0001). CONCLUSIONS: A gradual increase in assessed functional ß-cell capacity occurred after weight loss, becoming similar to that of NDC group participants by 12 months. This result was unchanged at 2 years with continuing remission of type 2 diabetes.

Hepatic Lipoprotein Export and Remission of Human Type 2 Diabetes after Weight Loss.

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 ß-cell function. Weight-related disordered fat metabolism appears to drive development and reversal of type 2 diabetes.

Understanding the mechanisms of reversal of type 2 diabetes.

Clinical and pathophysiological studies have shown type 2 diabetes to be a condition mainly caused by excess, yet reversible, fat accumulation in the liver and pancreas. Within the liver, excess fat worsens hepatic responsiveness to insulin, leading to increased glucose production. Within the pancreas, the ß cell seems to enter a survival mode and fails to function because of the fat-induced metabolic stress. Removal of excess fat from these organs via substantial weight loss can normalise hepatic insulin responsiveness and, in the early years post-diagnosis, is associated with ß-cell recovery of acute insulin secretion in many individuals, possibly by redifferentiation. Collectively, these changes can normalise blood glucose levels. Importantly, the primary care-based Diabetes Remission Clinical Trial (DiRECT) showed that 46% of people with type 2 diabetes could achieve remission at 12 months, and 36% at 24 months, mediated by weight loss. This major change in our understanding of the underlying mechanisms of disease permits a reassessment of advice for people with type 2 diabetes.

Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial.

BACKGROUND: The DiRECT trial assessed remission of type 2 diabetes during a primary care-led weight-management programme. At 1 year, 68 (46%) of 149 intervention participants were in remission and 36 (24%) had achieved at least 15 kg weight loss. The aim of this 2-year analysis is to assess the durability of the intervention effect. METHODS: DiRECT is an open-label, cluster-randomised, controlled trial done at primary care practices in the UK. Practices were randomly assigned (1:1) via a computer-generated list to provide an integrated structured weight-management programme (intervention) or best-practice care in accordance with guidelines (control), with stratification for study site (Tyneside or Scotland) and practice list size (>5700 or ≤5700 people). Allocation was concealed from the study statisticians; participants, carers, and study research assistants were aware of allocation. We recruited individuals aged 20-65 years, with less than 6 years' duration of type 2 diabetes, BMI 27-45 kg/m2, and not receiving insulin between July 25, 2014, and Aug 5, 2016. The intervention consisted of withdrawal of antidiabetes and antihypertensive drugs, total diet replacement (825-853 kcal per day formula diet for 12-20 weeks), stepped food reintroduction (2-8 weeks), and then structured support for weight-loss maintenance. The coprimary outcomes, analysed hierarchically in the intention-to-treat population at 24 months, were weight loss of at least 15 kg, and remission of diabetes, defined as HbA1c less than 6·5% (48 mmol/mol) after withdrawal of antidiabetes drugs at baseline (remission was determined independently at 12 and 24 months). The trial is registered with the ISRCTN registry, number 03267836, and follow-up is ongoing. FINDINGS: The intention-to-treat population consisted of 149 participants per group. At 24 months, 17 (11%) intervention participants and three (2%) control participants had weight loss of at least 15 kg (adjusted odds ratio [aOR] 7·49, 95% CI 2·05 to 27·32; p=0·0023) and 53 (36%) intervention participants and five (3%) control participants had remission of diabetes (aOR 25·82, 8·25 to 80·84; p<0·0001). The adjusted mean difference between the control and intervention groups in change in bodyweight was -5·4 kg (95% CI -6·9 to -4·0; p<0·0001) and in HbA1c was -4·8 mmol/mol (-8·3 to -1·4 [-0·44% (-0·76 to -0·13)]; p=0·0063), despite only 51 (40%) of 129 patients in the intervention group using anti-diabetes medication compared with 120 (84%) of 143 in the control group. In a post-hoc analysis of the whole study population, of those participants who maintained at least 10 kg weight loss (45 of 272 with data), 29 (64%) achieved remission; 36 (24%) of 149 participants in the intervention group maintained at least 10 kg weight loss. Serious adverse events were similar to those reported at 12 months, but were fewer in the intervention group than in the control group in the second year of the study (nine vs 22). INTERPRETATION: The DiRECT programme sustained remissions at 24 months for more than a third of people with type 2 diabetes. Sustained remission was linked to the extent of sustained weight loss. FUNDING: Diabetes UK.

Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent upon Capacity for ß Cell Recovery.

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 ß cell ability to recover long-term function persists after diagnosis, changing the previous paradigm of irreversible loss of ß cell function in type 2 diabetes.

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.

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.