The Real Cause of T2 Diabetes: Fat, Sugar or....

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The Real Cause of T2 Diabetes: Fat, Sugar or....

Postby JeffN » Wed Dec 06, 2017 10:51 am

The Real Cause of T2 Diabetes: Fat, Sugar or....


There seems to be this ‘diabetes war’ between fat vs sugar as the “cause” of T2 diabetes, somewhat fueled by the movie What The Health,

Seems to me, the main (but not only) issue is excess calories and excess body fat. Just cutting calories (sometimes dramatically) almost instantly puts diabetes into remission, regardless of the ratio of sugar/carb, fat or protein

1) Here's the data on a new study on the topic. The more weight they lose the more likely they are to be able to put their disease in remission and likely keep it there for a long time provided they keep the weight off:

• Weight gainers: 0% achieved remission (0/76 participants)
• 0-5 kg weight loss (0-11 lbs): 7% (6/89)
• 5-10 kg (11-22 lbs): 34% (19/56)
• 10-15 kg (22-33.1 lbs): 57% (16/28)
• 15+ kg (33.1 lbs): 86% (31/36)

"The program involved an initial 3-month phase of total diet replacement -- 825-853 kcal per day consisting of 59% carbohydrates, 13% fat, 26% protein, and 2% fiber. A food reintroduction period followed for 2 to 8 weeks, which consisted of a diet comprising of 50% carbs, 35% total fat, and 15% protein.

Medpage Article
Weight Management May Reverse T2D
Study participants achieved remission to non-diabetic state
https://www.medpagetoday.com/endocrinol ... etes/69657

Lancet Study
Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial
DOI: http://dx.doi.org/10.1016/S0140-6736(17)33102-1
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)33102-1/fulltext


2) In this small pilot study, they reversed diabetes with an 800 calorie diet

Reversal of type 2 diabetes in youth who adhere to a very-low-energy diet: a pilot study.
Diabetologia. 2017 Mar;60(3):406-415. doi: 10.1007/s00125-016-4163-5. Epub 2016 Nov 26.
https://www.ncbi.nlm.nih.gov/pubmed/27889809

Abstract
AIMS/HYPOTHESIS:
The aim of the study was to investigate whether a very-low-energy diet (VLED) is a feasible and acceptable treatment option for type 2 diabetes in children and adolescents, and whether adherence can lead to rapid weight loss, reversal of type 2 diabetes and reduced liver fat as seen in adult studies.

METHODS:
Eight participants with type 2 diabetes and obesity, aged 7-16 years, non-medicated (n = 1) or treated with metformin (n = 7) and in some cases insulin (n = 3), followed a VLED (<3360 kJ/day) for 8 weeks, then transitioned to a hypocaloric diet (∼6300 kJ/day) that they followed to 34 weeks. HbA1c, fasting glucose and 2 h post-glucose load plasma glucose (2hG) were determined from fasting blood and an OGTT. Liver fat concentration was quantified using proton magnetic resonance spectroscopy. Adherence was defined as ≥5% weight loss during the 8 week VLED.

RESULTS:
Adherers (n = 5) and non-adherers (n = 3) had median weight loss of 7.5% and 0.5%, respectively, at 8 weeks. Overall, HbA1c (mean [SE] 8.1% [0.7%] to 6.6% [0.5%]; p = 0.004) and 2hG (15.6 [1.6] mmol/l to 11.3 [1.0] mmol/l; p = 0.009) were significantly reduced at 8 weeks compared with baseline. Liver fat was also significantly reduced from baseline (14.7% [2.2%]) to 8 weeks (5.8% [1.7%]; p = 0.001). Only three out of eight participants met non-alcoholic fatty liver disease (NAFLD) criteria (≥5.5%) at 8 weeks, compared with eight out of eight at baseline. The three participants on insulin therapy at baseline were able to cease therapy during the 8 week VLED. At 34 weeks, adherers (n = 5) achieved 12.3% weight loss, none met NAFLD criteria and four did not meet American Diabetes Association criteria for type 2 diabetes.

CONCLUSIONS/INTERPRETATION:
A VLED appears to be a feasible treatment option for some youth with type 2 diabetes on metformin therapy. Youth who agree to participate and adhere to a VLED achieve rapid weight loss, dramatic reductions in liver fat and reversal of type 2 diabetes. This highlights the capacity of a VLED to be used as a first-line treatment option in newly diagnosed youth. A larger trial with a control group and longer follow-up will be required to encourage a change in standard treatment.


3) In this one, they used a 740 calorie diet

Six and 12 Weeks of Caloric Restriction Increases β Cell Function and Lowers Fasting and Postprandial Glucose Concentrations in People with Type 2 Diabetes.
J Nutr. 2015 Sep;145(9):2046-51. doi: 10.3945/jn.115.210617. Epub 2015 Aug 5.

https://www.ncbi.nlm.nih.gov/pmc/articl ... /26246321/

Abstract

BACKGROUND:
Caloric restriction alone has been shown to improve insulin action and fasting glucose metabolism; however, the mechanism by which this occurs remains uncertain.

OBJECTIVE:
We sought to quantify the effect of caloric restriction on β cell function and glucose metabolism in people with type 2 diabetes.

METHODS:
Nine subjects (2 men, 7 women) with type 2 diabetes [BMI (in kg/m(2)): 40.6 ± 1.4; age: 58 ± 3 y; glycated hemoglobin: 6.9% ± 0.2%] were studied using a triple-tracer mixed meal after withdrawal of oral diabetes therapy. The oral minimal model was used to measure β cell function. Caloric restriction limited subjects to a pureed diet (<900 kcal/d) for the 12 wk of study. The studies were repeated after 6 and 12 wk of caloric restriction.

RESULTS:
Fasting glucose concentrations decreased significantly from baseline after 6 wk of caloric restriction with no further reduction after a further 6 wk of caloric restriction (9.8 ± 1.3, 5.9 ± 0.2, and 6.2 ± 0.3 mmol/L at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.01) because of decreased fasting endogenous glucose production (EGP: 20.4 ± 1.1, 16.2 ± 0.8, and 17.4 ± 1.1 μmol · kg(-1) · min(-1) at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.03). These changes were accompanied by an improvement in β cell function measured by the disposition index (189 ± 51, 436 ± 68, and 449 ± 67 10(-14) dL · kg(-1) · min(-2) · pmol(-1) at baseline and after 6 and 12 wk of caloric restriction, respectively; P = 0.01).

CONCLUSIONS:
Six weeks of caloric restriction lowers fasting glucose and EGP with accompanying improvements in β cell function in people with type 2 diabetes. An additional 6 wk of caloric restriction maintained the improvement in glucose metabolism.


4) Here is a study on some ongoing work on reversing diabetes on a 600 calorie diet

Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol
Diabetologia. 2011 Oct; 54(10): 2506–2514.
Published online 2011 Jun 9. doi: 10.1007/s00125-011-2204-7
PMCID: PMC3168743

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168743/

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/m2, 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.

Here is the webpage of the scientific group that is doing this work

http://www.ncl.ac.uk/magres/research/di ... nformation

Here is the full text of the write up in Diabetes Care

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3609491/


5) I have always found the following study eye-opening in regard to this issue as it really challenges several concepts.

The study compared two diets both containing the same amount of calories (1100), and the same percentages of fat (11%), protein (19%) and carb (71%). The only difference was where the carbs came from. In one group, 43% of the calories came from white sugar. In the other diet, only 4% came from white sugar. Thats 118 grams (around 30 tsps) vs 11 grams (around 3 tsps)

Both groups experienced the same decreases in weight, blood pressure, percentage body fat,and the same changes in total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. There was no difference in the effect of either diet on fasting blood sugar (which went down in both groups)

Why? Total calories were restricted and both groups lost weight. Each group took in around 1100 calories and lost about 7 kgs (almost 15 bs) over the 6 weeks.

Metabolic and behavioral effects of a high-sucrose diet during weight loss
Am J Clin Nutr. 1997 Apr;65(4):908-15.
https://www.ncbi.nlm.nih.gov/pubmed/9094871

In response to evidence linking obesity and high amounts of dietary fat, the food industry has developed numerous reduced-fat and nonfat food items. These items frequently derive a relatively large percentage of their energy from sugars and the effect of these sugars on weight regulation is not well known. We studied the comparative effects of high- and low-sucrose, low-fat, hypoenergetic diets on a variety of metabolic and behavioral indexes in a 6-wk weight-loss program. Both diets contained approximately 4606 kJ energy/d with 11% of energy as fat, 19% as protein, and 71% as carbohydrate. The high-sucrose diet contained 43% of the total daily energy intake as sucrose; the low-sucrose diet contained 4% of the total daily energy intake as sucrose. Twenty women aged 40.6 +/- 8.2 y (mean +/- SD) with a body mass index (in kg/m2) of 35.93 +/- 4.8 consumed the high-sucrose diet; 22 women aged 40.3 +/- 7.3 y with a body mass index of 34.93 +/- 4.4 consumed the low-sucrose diet. Mixed-design analysis of variance showed a main effect of time (P < 0.01), with both diet groups showing decreases in weight, blood pressure, resting energy expenditure, percentage body fat, free triiodothyronine (FT3), urinary norepinephrine, and plasma lipids. Small but significant interactions were found between group and time in total cholesterol (P = 0.009) and low-density lipoprotein (LDL) (P = 0.01). Both groups showed decreases in depression, hunger, and negative mood, and increases in vigilance and positive mood with time (P < 0.01). Results showed that a high sucrose content in a hypoenergetic, low-fat diet did not adversely affect weight loss, metabolism, plasma lipids, or emotional affect.


6) From my colleague Jay Kenney, PhD, RDN, Director of Nutrition Research at the Pritikin Longevity Center. (PLC) in a recent discussion on the topic.

".. type 2 DM is driven primarily by excessive calorie intake and excessive body fat stores. Those two factors are far more important than any factors that can play a minor role in the development of insulin resistance and beta-cell failure. We've seen much improved insulin sensitivity for decades at the PLCs when people consume far fewer calories and that happens before they have lost much weight. However, if one stays on a low calorie intake and continues losing more weight you have a win-win situation that allows most type 2 DM patients with sufficient remaining beta-cell function to get off their diabetes meds as insulin resistance is largely reversible with a healthy diet and exercise program provided it reduces calorie intake and leads to long term weight control.

The ratio of FAT/PRO/CHO is far less important. However, at exactly the same calorie intake in weight stable people increasing fat (and especially SFA) at the expense of CHO (perhaps less so fructose rich CHO) seems to slightly increase insulin resistance. Of course, even on the Atkins diet people who lost a lot of weight often got off their diabetes meds so any suggestion that the type of calories one consumes is more important than total calorie intake and change in body fat stores seems rather naïve. Also in weight stable people upping exercise does modestly reduce insulin resistance even though calorie intake does go up to prevent weight loss. Even so some of the effect of exercise may be mediated by increased lean tissue and reduced fat even though body weight stays stable. There is also evidence that a high intake of protein (especially BCAA and specifically valine) can increase insulin resistance in muscle cells directly as the valine is catabolized to HIB. But increased body fat may lead to increased insulin resistance by reducing the ability of insulin to reach muscle cells"


Considering all the above which show that we can easily reverse T2 diabetes in just a week or two using a very low calorie diet regardless of the macronutrient ratios, I think the argument over fat vs sugar as the primary cause of T2 diabetes, is very misguided.

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Re: The Real Cause of T2 Diabetes: Fat, Sugar or....

Postby JeffN » Fri Aug 03, 2018 6:11 am

Remission of Human Type 2 Diabetes Requires Decrease in Liver and Pancreas Fat Content but Is Dependent upon Capacity for β Cell Recovery
Cell Metabolism
Published:August 02, 2018
DOI:https://doi.org/10.1016/j.cmet.2018.07.003

Highlights
- 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

Summary
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/m 2, 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/m 2, 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.

https://www.cell.com/cell-metabolism/fu ... 50-4131(18)30446-7
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Re: The Real Cause of T2 Diabetes: Fat, Sugar or....

Postby JeffN » Sat Mar 30, 2019 11:25 am

Immediate and long-term effects of a very-low-calorie diet on diabetes remission and glycemic control in obese Thai patients with type 2 diabetes mellitus.
Food Sci Nutr. 2019 Feb 11;7(3):1113-1122. doi: 10.1002/fsn3.956. eCollection 2019 Mar.
PMID: 30918654

https://onlinelibrary.wiley.com/doi/epd ... 2/fsn3.956

Abstract

AIM:
A very-low-calorie diet (VLCD) can reverse the underlying defects of type 2 diabetes mellitus (DM) in obese subjects. We determined the efficacy, safety, and durability of VLCD in Thai patients with DM and obesity.

METHODS:
Twenty Thai patients with DM and obesity were enrolled. After a 2-week trial, VLCD (600 kcal/day) was continued for 8 weeks, followed by a 4-week transition period. Data on diabetes remission (fasting plasma glucose level <126 mg/dl and HbA1c <6.5% without the use of glucose-lowering medications), glycemic control, metabolic parameters, and quality of life (QOL) were collected along with indices of insulin resistance (IR) and beta cell function. Glycemic control 12 months after discontinuation of VLCD was also examined.

RESULTS:
Among 19 patients (age 48 ± 2 years, BMI 27.7 kg/m2) who completed the study, rapid improvement in glycemic control was observed in the first 2 weeks of VLCD. At both 8 and 12 weeks, diabetes remission was achieved in 79%. Significant weight loss was accompanied by a significant reduction in IR and an increase in beta cell function, starting at 4 weeks of VLCD. QOL also significantly increased. At 12 months after VLCD, however, DM remission was achieved in approximately 30%.

CONCLUSION:
Very-low-calorie diet was effective and safe in inducing short-term diabetes remission in Thai subjects by ameliorating beta cell function and IR. Optimal long-term glycemic control was potentially durable as one-third of subjects remained without diabetes medication 12 months after VLCD.


And

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
Published:March 06, 2019
The Lancet. VOLUME 7, ISSUE 5, P344-355, MAY 01, 2019
DOI:https://doi.org/10.1016/S2213-8587(19)30068-3

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/m 2, 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 HbA 1c 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 HbA 1c 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.
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Re: The Real Cause of T2 Diabetes: Fat, Sugar or....

Postby JeffN » Tue Jan 14, 2020 11:15 am

Hepatic Lipoprotein Export and Remission of Human Type 2 Diabetes after Weight Loss Published:December 19, 2019
DOI:https://doi.org/10.1016/j.cmet.2019.11.018

Highlights

- 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
Summary

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.

https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30662-X#sec4

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Re: The Real Cause of T2 Diabetes: Fat, Sugar or....

Postby JeffN » Sat Oct 10, 2020 8:54 am

2-year remission of type 2 diabetes and pancreas morphology: a post-hoc analysis of the DiRECT open-label, cluster-randomised trial
Published:October 05, 2020
DOI:https://doi.org/10.1016/S2213-8587(20)30303-X
https://www.thelancet.com/journals/land ... 13-8587(20)30303-X/fulltext

Summary

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 (HbA 1c <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. β-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 cm 3 (SD 16·0) in all participants with type 2 diabetes and 79·8 cm 3 (14·3) in the NDC group (p<0·0001). At 24 months, pancreas volume had increased by 9·4 cm 3 (95% CI 6·1 to 12·8) in responders compared with 6·4 cm 3 (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.


Pancreas Function Could Return to Normal Following Diabetes Remission, Study Suggests
October 8, 2020
Patrick Campbell
An analysis of data from DiRECT suggests diabetes remission was linked to restoration of pancreas size and function.

https://www.endocrinologynetwork.com/vi ... y-suggests
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Re: The Real Cause of T2 Diabetes: Fat, Sugar or....

Postby JeffN » Sun Nov 22, 2020 8:55 am

https://www.atherosclerosis-journal.com/article/S0021-9150(16)30048-X/fulltext


Review article
Imbalanced insulin action in chronic over nutrition: Clinical harm, molecular mechanisms, and a way forward
Atherosclerosis 247 (2016) 225e282

Highlights: this review covers

•Normal, balanced insulin action in liver, endothelium, brain, and elsewhere.

•What goes wrong – clinically and molecularly – in states of chronic overnutrition.

•How overnutrition and underexertion have become such widespread problems.

•What we might do next to solve this man-made epidemic.

The growing worldwide prevalence of overnutrition and underexertion threatens the gains that we have made against atherosclerotic cardiovascular disease and other maladies. Chronic overnutrition causes the atherometabolic syndrome, which is a cluster of seemingly unrelated health problems characterized by increased abdominal girth and body-mass index, high fasting and postprandial concentrations of cholesterol- and triglyceride-rich apoB-lipoproteins (C-TRLs), low plasma HDL levels, impaired regulation of plasma glucose concentrations, hypertension, and a significant risk of developing overt type 2 diabetes mellitus (T2DM). In addition, individuals with this syndrome exhibit fatty liver, hypercoagulability, sympathetic overactivity, a gradually rising set-point for body adiposity, a substantially increased risk of atherosclerotic cardiovascular morbidity and mortality, and e crucially e hyperinsulinemia.

Many lines of evidence indicate that each component of the atherometabolic syndrome arises, or is worsened by, pathway-selective insulin resistance and responsiveness (SEIRR). Individuals with SEIRR require compensatory hyperinsulinemia to control plasma glucose levels. The result is overdrive of those pathways that remain insulin-responsive, particularly ERK activation and hepatic de-novo lipogenesis (DNL), while carbohydrate regulation deteriorates. The effects are easily summarized: if hyper- insulinemia does something bad in a tissue or organ, that effect remains responsive in the atherome- tabolic syndrome and T2DM; and if hyperinsulinemia might do something good, that effect becomes resistant. It is a deadly imbalance in insulin action. From the standpoint of human health, it is the worst possible combination of effects.

In this review, we discuss the origins of the atherometabolic syndrome in our historically unprece- dented environment that only recently has become full of poorly satiating calories and incessant en- ticements to sit. Data are examined that indicate the magnitude of daily caloric imbalance that causes obesity. We also cover key aspects of healthy, balanced insulin action in liver, endothelium, brain, and elsewhere. Recent insights into the molecular basis and pathophysiologic harm from SEIRR in these organs are discussed. Importantly, a newly discovered oxide transport chain functions as the master regulator of the balance amongst different limbs of the insulin signaling cascade. This oxide transport chain e abbreviated ‘NSAPP’ after its five major proteins e fails to function properly during chronic overnutrition, resulting in this harmful pattern of SEIRR.

We also review the origins of widespread, chronic overnutrition. Despite its apparent complexity, one factor stands out. A sophisticated junk food industry, aided by subsidies from willing governments, has devoted years of careful effort to promote overeating through the creation of a new class of food and drink that is low- or no-cost to the consumer, convenient, savory, calorically dense, yet weakly satiating. It is past time for the rest of us to overcome these foes of good health and solve this man-made epidemic.



7. Summary and a way forward

Decades of research have clarified the atherometabolic syn- drome. The underlying cause is chronic overnutrition. Many lines of evidence indicate that each component of the syndrome arises, or is worsened by, SEIRR. The result is compensatory hyperinsulinemia to control plasma glucose levels, but then overdrive of insulin- responsive pathways, such as ERK activation and hepatic de-novo lipogenesis. Unfortunately, if insulin does something bad in a tis- sue or organ, that effect remains responsive in the atherometabolic syndrome; and if insulin does something good, that effect becomes resistant. It is a deadly imbalance in insulin action. From the stand- point of human health, it is the worst possible combination of effects. Several major mysteries remain. First is the molecular origin of the dysfunction in the NSAPP oxide transport chain that prevents it from normally inactivating PTEN and PTPases upon insulin stimu- lation. If this defect turns out to be the result of PPP5C over- expression, as we have inferred, then the cause of its overexpression will need to be uncovered. If some other process is responsible for dysfunction of the NSAPP oxide transport chain, then it will need to be found. The process that disrupts the NSAPP oxide transport chain may be a crucial, but unidentified, sensor of caloric excess that then causes metabolic derangements (Sections 2.4 and 4.5).

A second mystery is how our calorie-rich, chair-enticing environment disrupts the precise, semi-autonomic regulation of energy balance (Sections 1.4, 3.3, and 5.5). For most of the population, our new environment raises the set-points for weight and adiposity. Is it because of SEIRR combined with leptin resistance in the hypo- thalamus? Which region? Defects in insulin-based reward cir- cuitry? Overwhelming hedonic cues?

Third, how does positive caloric imbalance rapidly cause metabolic deterioration, and how does negative caloric imbalance rapidly improve the metabolic state? Short-term effects of caloric imbalance on the NSAPP oxide transport chain will be an attractive area for future study. Unfortunately, systemic metabolic improve- ment does not necessarily mean that the central set-point for weight and adiposity has been lowered. Calorically restricted in- dividuals often remain hungry. Do insulin and leptin signaling in the brain remain defective during negative caloric imbalance even as the rest of the body improves [772]

Fourth, how does the most successful current weight-loss therapy e bariatric surgery e appear to lower the homeostatic set-point? Can non-surgical alternatives be found that trigger the same mechanisms [889,890]

Fifth, what roles, if any, do ectopic lipids, lipotoxicity, activation of PKC isoforms, impaired mitochondrial performance, low-grade maladaptive inflammation, ER stress, and other well-known the- ories of poor glucose handling play in the devastating pattern of imbalanced insulin action that is characteristic of the atherometa- bolic syndrome

The worldwide prevalence of the atherometabolic syndrome has been accelerated by a sophisticated junk food industry, aided by subsidies from willing governments. This industry and its partners have devoted years of careful study and effort to promote seem- ingly modest e but consistent e overeating through the creation of inexpensive, convenient, savory, calorically dense, yet weakly satiating cuisine. It is past time for the rest of us to overcome these foes of good health and solve this man-made epidemic
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Re: The Real Cause of T2 Diabetes: Fat, Sugar or....

Postby JeffN » Tue Jul 13, 2021 7:43 pm

“each kg of weight gained annually over 10 years was associated with a 49% increase in risk of developing diabetes in the subsequent 10 years. Each kg of of weight gained annually over 10 years was associated with a 49% increase in risk of developing diabetes in the subsequent 10 years. Each kg of weight lost annually over 10 years was associated with a 33% lower risk of diabetes in the subsequent 10 years.”

Relation of weight gain and weight loss on subsequent diabetes risk in overweight adults
J Epidemiol Community Health
2000 Aug;54(8):596-602. doi: 10.1136/jech.54.8.596.

https://pubmed.ncbi.nlm.nih.gov/10890871/

Abstract

Study objective: To determine whether long term weight gain and weight loss are associated with subsequent risk of type 2 diabetes in overweight, non-diabetic adults.

Design: Prospective cohort. Baseline overweight was defined as BMI>/=27.3 for women and BMI>/=27. 8 for men. Annual weight change (kg/year) over 10 years was calculated using measured weight at subjects' baseline and first follow up examinations. In the 10 years after measurement of weight change, incident cases of diabetes were ascertained by self report, hospital discharge records, and death certificates.

Setting: Community.

Participants: 1929 overweight, non-diabetic adults.

Main results: Incident diabetes was ascertained in 251 subjects. Age adjusted cumulative incidence increased from 9.6% for BMI<29 to 26. 2% for BMI>/=37. Annual weight change over 10 years was higher in subjects who become diabetic compared with those who did not for all BMI<35. Relative to overweight people with stable weight, each kg of weight gained annually over 10 years was associated with a 49% increase in risk of developing diabetes in the subsequent 10 years. Each kg of weight lost annually over 10 years was associated with a 33% lower risk of diabetes in the subsequent 10 years.

Conclusions: Weight gain was associated with substantially increased risk of diabetes among overweight adults, and even modest weight loss was associated with significantly reduced diabetes risk. Minor weight reductions may have major beneficial effects on subsequent diabetes risk in overweight adults at high risk of developing diabetes.
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JeffN
 
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Re: The Real Cause of T2 Diabetes: Fat, Sugar or....

Postby JeffN » Wed Sep 01, 2021 6:36 am

Have you put your diabetes in remission?

We now have a formal definition for the remission of diabetes from the European Association for the Study of Diabetes (EASD) and the American Diabetes Association (ADA)

1) An HbA1c <48 mmol/mol (6.5%)
2) Measured at least 3 months after cessation of glucose-lowering medications

Consensus report: definition and interpretation of remission in type 2 diabetes. Diabetologia (2021). Published: 30 August 2021

This group proposed ‘remission’ as the most appropriate descriptive term, and HbA1c <48 mmol/mol (6.5%) measured at least 3 months after cessation of glucose-lowering pharmacotherapy as the usual diagnostic criterion.

https://link.springer.com/article/10.10 ... 21-05542-z
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