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Friday, 23 January 2015

Testing the effect of a high fat diet in severe type 2 diabetes - Garg and Unger metabolic ward study from 1988

It's all very well to test the metabolic effects of high-fat diets in RCTs. There are usually beneficial results in type 2 diabetes, but compliance is limited. The trial isn't showing what the diet does, but what effect the advice has on people who may be more or less indifferent to it. In fact, it's amazing these trials produce the positive results they do.
A metabolic ward study involves subjects who follow the diet because they have nothing else to eat; all variables such as exercise are kept constant. Because you don't get huge numbers volunteering for these studies, and the cost is high because of the round-the-clock supervision and testing, the crossover method is normally used. Half the subjects eat the test diet, the other half the control, then they switch over. Results from the end of each period in both groups are averaged.
This is a 1988 study authored by Abhimanyu Garg, Roger Unger and 3 colleagues.

N Engl J Med. 1988 Sep 29;319(13):829-34.

Comparison of a high-carbohydrate diet with a high-monounsaturated-fat diet in patients with non-insulin-dependent diabetes mellitus.

Garg A1, Bonanome A, Grundy SM, Zhang ZJ, Unger RH


We compared a high-carbohydrate diet with a high-fat diet (specifically, a diet high in monounsaturated fatty acids) for effects on glycemic control and plasma lipoproteins in 10 patients with non-insulin-dependent diabetes mellitus (NIDDM) receiving insulin therapy. The patients were randomly assigned to receive first one diet and then the other, each for 28 days, in a metabolic ward. In the high-carbohydrate diet, 25 percent of the energy was in the form of fat and 60 percent in the form of carbohydrates (47 percent of the total energy was in the form of complex carbohydrates); the high-monounsaturated-fat diet was 50 percent fat (33 percent of the total energy in the form of monounsaturated fatty acids) and 35 percent carbohydrates. The two diets had the same amounts of simple carbohydrates and fiber. As compared with the high-carbohydrate diet, the high-monounsaturated-fat diet resulted in lower mean plasma glucose levels and reduced insulin requirements, lower levels of plasma triglycerides and very-low-density lipoprotein cholesterol (lower by 25 and 35 percent, respectively; P less than 0.01), and higher levels of high-density lipoprotein (HDL) cholesterol (higher by 13 percent; P less than 0.005). Levels of total cholesterol and low-density lipoprotein (LDL) cholesterol did not differ significantly in patients on the two diets. These preliminary results suggest that partial replacement of complex carbohydrates with monounsaturated fatty acids in the diets of patients with NIDDM does not increase the level of LDL cholesterol and may improve glycemic control and the levels of plasma triglycerides and HDL cholesterol.

Thanks to Ivor Cummings, I have the full-text pdf, and it's very interesting.
The other dietary variables are well controlled for.

The types of fatty acids, if that makes any difference, are also well-matched between diets (low fat diet used corn and palm oils, high fat diet used olive oil, so neither was high omega-3).
The results are fascinating (this is the average from the last week of each period, days 21-28).

Who knew that a urinary glucose output of 142 mg/day was normal on a high-carbohydrate diet in subjects with "non-insulin dependent diabetes mellitus treated with insulin" - to disappear completely on a diet with 50% of calories from olive oil?
Oh, and the base line? That was after a week on the diet recommended by the ADA in 1988, which was the lead-in diet.
What about lipids? They improved too:

What's especially interesting aboout these lipid results is the comparison between this study (second phase T2D) and Garg and Unger's 1992 study of the same diets in mild (first phase) T2D. In mild T2D, a high MUFA diet improved lipids but did not influence insulin sensitivity. This seems consistent with high-carb/high-calorie diets and hyperinsulinaemia in those prone to diabetes driving lipotoxicity, when then produces the phase 2 phenomenon of hyperglycaemia plus hyperlipidaemia by altering the ratio of alpha- to beta- cell sensitivity and activity. Dietary carbohydrate drives fat which drives endogenous glucose.

The authors of the 1988 paper sum up thus:

Abhimanyu Garg has authored this convenient review of all the studies using a high-MUFA diet for Type 2 NIDDM.
It includes this classic line:
 "The improvement in the glycemic profile with high-monounsaturated-fat diets may not be related to changes in insulin sensitivity but to a reduction in the carbohydrate load, which patients with type 2 diabetes may not be able to handle readily because of severe insulin resistance and b cell defects."

Of course what we lack is a comparative series of studies with high SFA diets, or indeed diets in the normal range of mixed SFA, MUFA and PUFA. Does the type of fat matter if carbohydrate is low enough? Quite possibly not, at least for the majority. Is 35% carbohydrate low enough to see the full benefit of a high-fat diet? Maybe not, but the results, after only 28 days, were impressive enough.


Charles Grashow said...

What are your thoughts on this diet?

George Henderson said...

"For both groups, energy intake was restricted by limiting calories to 1900 kcal/day and 1700 kcal/day for males and females, respectively. The diets were isocaloric but differed in nutrient composition. Ma-Pi 2 diet derived 72% of energy from carbohydrate, 18% from fat, and 10% energy from protein, fiber equal to 30 g/1000 kcal, while the control diet 50% from carbohydrate, 20% from protein, and 30% from fat, fiber ≥20 g/1000 kcal. Alcohol consumption was forbidden. Both diets provided 5 meals per day, with energy intake being divided between meals, 20% calories at breakfast, 30% calories at lunch and 30% calories at dinner. Two snacks were administered at approximately 2.5 hours after breakfast and lunch, respectively, each contributing 10% of the calories per day".

It does not surprise me that a low-fat hgh-fibre macrobiotic diet was superior to the usual recommendations, especially in these relatively mild cases (no insulin).
However in the large UK studies like the Belfast one, an improvement in insulin sensitivity early in a dietary intervention doesn't prevent later decline. This is probably because the roots of the problem go deeper than peripheral glucose disposal.
There are clearly benefits from calorie restriction in T2D and it's worth asking whether a high-fibre wholefood intervention is actually reducing energy intake beyond that calculated from the food supplied.

Note that the high-carbohydrate diet in the Garg and Unger study was clearly superior to the baseline diet, which was based on then diabetes recommendations (a longer lead-in than one week, and a comparison of all 3 diets would have been helpful).
If there hadn't been a high-MUFA diet to blow it out of the water, conclusions would all have been in favour of the high-carbohydrate diet.

If there are autoimmune risks from increasing the grain content of the diet, or risks from mineral and vitamin deficiencies on the macrobotic diet, these may not show up right away.

Charles Grashow said...

This study included 16 type 2 diabetics that were all receiving insulin therapy at baseline. There were 3 men and 13 women, average age of 60 with a range of diabetes duration from 9 to 31 years. Their mean weight was 69kg with a BMI of 28. Six months on Ma-Pi 2.

Weight loss: 6.25 kg, ~14 lbs
Average HbA1c: 12.60 to 5.73

Medication Status at 6 Months: NO INSULIN USE by any subject at the end of the intervention. Dietary therapy ONLY for 12 of 16 or 75% of subjects. Four subjects were switched to glibenclamide.

Daily DIABETIC MEDICATION consumption was high at onset: 53 patients used a total of 1341 insulin units (mean consumption: 25 u/person and 0.3 u/kgWt); 60 patients consumed 200 hypoglycemic pills (mean consumption 4 tabs/person).
Serum glucose, lipids, and other indicators reflected a non-optimal metabolic control at onset. The high glycemia value at onset (8.35 mmol/L) dropped fast during the first 3 days of intervention, parallel to the insulin consumption reduction. After 21 days, the 2 mmol/L reduction (23%) was highly significant; 3 months later it was more evident (2.7 mmol/L, 32%), reaching values inside the metabolic control interval.
The high fiber, Mn, Mg, and Zn intake and the reduced fat and protein content of the diet have contributed to the observed decrease of the insulin demand. Only after 21 days, patients were able to control glycemia, serum lipids levels, and BLOOD PRESSURE. The fact that patients diminished further the insulin doses at 3 months indicates that they continued carrying out well enough their diet at home in spite of slightly dietary transgressions.

George Henderson said...

That sounds like results consistent with calorie restriction.
How were subjects selected?
I find it hard to believe that patients chosen at random would adhere to this diet this consistently, given the relatively high dropout rates with more palatable diets.
But if you can find self-selected subjects, you can work wonders with a wide range of a approaches.

George Henderson said...

Ma Pi 2 is named after the institute's founder

Considering the grief some people give Weston A Price or indeed Gary Taubes, Ma Pi's story should inspire confidence.
Wholefood or raw food vegans are not going to get type 2 diabetes easily. Maybe worth doing as a short intervention if nothing else works.

PhilT said... is interesting,

"Linear regression analysis showed that the greater the carbohydrate intake, the greater the HbA1c levels at baseline (P = 0.001). Also, the greater the reduction in carbohydrate intake (g/day), the greater the decrease in HbA1c levels (P < 0.001), but ΔHbA1c was not significantly influenced by changes in other macronutrient intakes (g/day)."

They stratified subjects according to initial HbA1c and treated them differently.

Evelyn aka CarbSane said...

"Who knew that a urinary glucose output of 142 mg/day was normal on a high-carbohydrate diet in subjects with "non-insulin dependent diabetes mellitus treated with insulin""

That's 0.142 grams of glucose over a 24 hour period. Which, is normal for anyone:

"Under normal circumstances, the kidney reabsorbs approximately 180 g of glucose from the glomerular filtrate each day. The glucose transporters in the renal proximal tubule ensure that less than 0.5 g/day (range 0.03-0.3 g/d) is excreted in the urine of healthy adults. Whereas mild renal glucosuria is relatively frequent, heavy glucosuria is extremely rare."

George Henderson said...

It disappeared when carbohydrate was significantly reduced. So it's still reflecting glucose tolerance or disposal even at low levels. In the 3 studies in which urinary glucose was measured it correlated with dietary carbohydrate.

George Henderson said...

Summing up what I've learned about the Ma-Pi studies:
Carried out by members of the macrobiotic movement.
Apart from Italian study take place in countries (China, Cuba, Ghana) with governments friendly to the macrobiotic movement. Likely because of its agricultural aspects.
Not controlled, randomised or blinded.
Not yet at stage of being tested skeptically by scientists not invested.
Plenty of scope for publication bias.
None of which means it's not legit, just that it's passed very few of the hurdles that one needs to clear to have a method accepted.

George Henderson said...

About the mild glycosuria:
"Dogs left with 20 per cent of their pancreas or more did not develop diabetes. The fate of those with 80–90 per cent of their pancreas removed depended on what they ate. On a low-carbohydrate diet, they remained relatively well, like middle-aged humans with diabetes — since Eskimos lived on very little carbohydrate, Allen called this an Eskimo diet. Large amounts of carbohydrate (a Hindu diet) wore out the pancreas and what had originally been mild diabetes turned into the severe pancreatic form. However, if the same animals were fed a high fat diet, the glycosuria disappeared or was greatly reduced."
It is interesting that this reduction in glycosuria on a high fat diet is not dependent on such glycosuria being significant to begin with, and is seen with regard to glycosuria that is within the normal range for healthy people.

@ PhilT, thanks for the link - sounds like Allen's Hindu diet. And the soft-drink ketosis - that's interesting

Charles Grashow said...

Scientific method: Statistical errors
P values, the 'gold standard' of statistical validity, are not as reliable

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