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Internist Departement Jurnal Reading

Endocrine-Metabolic Sub-Department

Mulawarman University Medical Faculty

RSUD A. Wahab Sjahranie

Effect Of A High-Protein, Low-Carbohydrate Diet

On Blood Glucose Control in PeopleWith Type 2 Diabetes

Oleh


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Oleh

LEMBAR PENGESAHAN

Jurnal Reading

Effect Of A High-Protein, Low-Carbohydrate Diet On Blood

Glucose Control in People With Type 2 Diabetes

Dibawakan Dalam Rangka Tugas Kepaniteraan Klinik

Laboratorium Ilmu Penyakit Dalam

Fakultas Kedokteran Universitas Mulawarman

RSUD Abdul Wahab Sjahranie

Oleh


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Effect of a High-Protein, Low-Carbohydrate Diet onBlood Glucose Control in People With Type 2 DiabetesMary C. Gannon1,2,3 and Frank Q. Nuttall1,3

There has been interest in the effect of various types

and amounts of dietary carbohydrates and proteins onblood glucose. On the basis of our previous data, wedesigned a high-protein/low-carbohydrate, weight-main-taining, nonketogenic diet. Its effect on glucose controlin people with untreated type 2 diabetes was deter-mined. We refer to this as a low-biologically-available-glucose (LoBAG) diet. Eight men were studied using arandomized 5-week crossover design with a 5-weekwashout period. The carbohydrate:protein:fat ratio ofthe control diet was 55:15:30. The test diet ratio was20:30:50. Plasma and urinary -hydroxybutyrate weresimilar on both diets. The mean 24-h integrated serumglucose at the end of the control and LoBAG diets was198 and 126 mg/dl, respectively. The percentage ofglycohemoglobin was 9.8 0.5 and 7.6 0.3, respec-tively. It was still decreasing at the end of the LoBAGdiet. Thus, the final calculated glycohemoglobin wasestimated to be 6.35.4%. Serum insulin was de-creased, and plasma glucagon was increased. Serumcholesterol was unchanged. Thus, a LoBAG diet in-gested for 5 weeks dramatically reduced the circulating

glucose concentration in people with untreated type 2diabetes. Potentially, this could be a patient-empower-ing way to ameliorate hyperglycemia without pharmaco-logical intervention. The long-term effects of such a dietremain to be determined. Diabetes 53:23752382, 2004

(5). This seems to be due largely to a rapid, progressive

decrease in the rate of glycogenolysis (5,6). Hepatic gly-cogen stores in turn are dependent on the content ofcarbohydrate in the diet (6). Thus, a reduced-carbohydratediet should result in a lower overnight fasting glucoseconcentration.

To test the hypothesis that a diet that is low in carbo-hydrate and particularly low in food-derived glucose couldlower both the fasting and the postprandial blood glucosein people with type 2 diabetes, we designed a low-carbohydrate diet in which readily digestible starch-con-

taining foods have been de-emphasized. However, thecarbohydrate content is sufficient to prevent ketosis. Thisis in contrast to the low-carbohydrate diets being advo-cated for weight loss (7). We refer to this as a low-biologically-available-glucose (LoBAG) diet. In our study,we also attempted to ensure weight stability. The effect of5 weeks of this diet on percentage glycohemoglobin and24-h glucose, insulin, C-peptide, -hydroxybutyrate, gluca-gon, triacylglycerol, and nonesterified fatty acid (NEFA)

profiles in eight men with untreated type 2 diabetes isreported. Urea, creatinine, uric acid, and other data relatedto the metabolism of protein after ingestion of the LoBAGdiet will be reported in a subsequent publication.


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Participants were randomized to begin the study with either the LoBAG or

the control diet by aflip of a coin. Six participants started on the LoBAG diet,

and five participants started on the control diet. Unfortunately, three of the

participants who started on the control diet did not complete the study for

personal reasons (death of spouse, move across country, chose not tofinish).Therefore, the data are presented on eight participants who completed both

arms of the study. Participants were admitted to the SDTU on the evening

before the study. The next day, standardized meals that contained 55%

carbohydrate, 30% fat, and 15% protein were given for breakfast, lunch, and

dinner at 0800, 1200, and 1800. Participants were asked to remain in the SDTU

during the study period with minimal activity.

On the second day in the SDTU, standardized meals again were given. This

diet was similar for both baseline studies and is referred to as control/pre

andLoBAG/pre diet in the figures, depending on which study diet followed

the inpatient stay. In addition to the meals at 0800, 1200 and 1800, snacks were

given at 1600 and 2100. Blood was obtained fasting at 0730, 0745, and 0800,every 15 min for the first hour after meals, every 30 min for the next 2 h, and

then hourly until the next meal. Blood was drawn at a total of 46 time points.

After this 24-h data accumulation period, the participants were sent home with

all of the necessary food for the next 23 days as appropriate for the diet to

which they were randomized

TABLE 1Patient characteristics

PatientAge

(years)Heightin (cm)

Weightlb (kg)

BMI(kg/m2)

tGHb(%)

Duration ofdiabetes

(months) Concomitant diseases Medications

1 69 74 (188) 221 (100) 27 8.7 60 Hypertension, dyslipidemia,coronary heart disease

Simvastatin, lisinopril,rabeprazole, ASA

2 72 69 (165) 239 (109) 35 10.0 12 Chronic obstructivepulmonary disease

Terazosin

3 51 68 (173) 181 (82) 27 8.6 12 None ASA, naproxen4 66 72 (183) 196 (89) 27 9.0 180 Hypertension None5 82 71 (180) 204 (93) 28 11.2 48 None Lisinopril, ASA 6 56 72 (183) 267 (121) 35 10.1 24 Obesity, dyslipidemia None

7 51 66 (168) 195 (89) 31 10.0 14 None ASA, naproxen8 59 67 (170) 233 (106) 36 9.4 19 Hypertension, obesity LisinoprilMean 63.3 70 (176) 217 (99) 31 9.6 46Range 5182 6674

(168188)181267(82121)

2736 8.611.2 12180

ASA, acetylsalicylic acid.

LoBAG DIET AND GLUCOSE CONTROL


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M.C. GANNON AND F.Q. NUTTALL


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(3,023 160 mg h dl1 [168 8.9 mmol h l1]; P0.0004 vs. the 5-week postcontrol and P 0.0001 vs.

pre-LoBAG). On the basis of these integrated areas, themean glucose concentration over the 24-h periods of studywas reduced from 198 to 126 mg/dl (117 mmol/l) after 5weeks on the LoBAG diet, a 36% decrease (P 0.0001).

The mean fasting insulin concentrations before andafter 5 weeks on both the control and the LoBAG dietswere identical (12 2 U/ml [72 12 pmol/l]; Fig. 3). Themean 24-h integrated insulin area response above thefasting value was similar after the pre- and postcontrol diet

response was similar to the control for the first hour afterbreakfast. Subsequently, the glucagon concentration washigher at every time point until 0700 the next morning,except for one time point after dinner. Both the net and the

total glucagon area responses were significantly increasedafter the LoBAG diet (P 0.05).

The mean fasting NEFA concentrations were 765 67,654 59, 718 70, and 593 50 Eq/l, before and afterthe control and LoBAG diets, respectively (data notshown). These differences were not statistically significant(P 0.05). The 24-h excursions were similar on thecontrol and LoBAG prediet days. When the LoBAG dietwas ingested, the fasting NEFA was lower and the in-

crease after the lunch meal was attenuated, as was thedecrease before dinner. The rise after dinner was morerapid and reached a higher concentration.

The mean 24-h integrated net NEFA area responseswere 5,323 1,187, 2,468 693, 4,525 1,660, and80 1,809 Eq h l1 before and after the control andLoBAG diets, respectively. The small positive area re-sponse after the LoBAG diet was statistically significantlydifferent compared with the response before the LoBAGdiet (P 0.05). Total areas were not statistically different

from one another.The mean fasting triacylglycerol concentrations were

264 36, 226 32, 246 27, and 149 23 mg/dl beforeand after the control and LoBAG diets, respectively (Fig.6). The fasting triacylglycerol concentration was signifi-cantly lower after 5 weeks on the LoBAG diet (P 0.05).

After ingestion of either diet, the triacylglycerol concen-tration increased until 1200 1400, decreased at 2000 2200, increased slightly at 2400, and subsequently

returned to the fasting value by 0800 the next morning.The mean 24-h integrated net triacylglycerol area re-sponse was not significantly different between diets. How-ever, the mean 24-h integrated total area response wassignificantly lower after 5 weeks on the LoBAG diet (P

FIG. 4. Mean %tGHb response during the 5 weeks of the control (E) or

LoBAG diet (F). *The tGHb on the test diet was significantly lower atweeks 3, 4, and 5 vs. the control diet (P < 0.05).



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lin secretion in people with type 2 diabetes (19). Thedecrease in integrated insulin concentration in the presentstudy undoubtedly is due to the reduced food-derivedglucose content of the diet. Dietary fat does not stimulate

insulin secretion (20), or it facilitates a modest increase(4,21,22). Fructose (2,23) and galactose (24) ingestion alsoresults in only a small increase in insulin concentration.

The serum total, LDL, and HDL cholesterol concentra-tions did not change significantly when the fat content ofthe diet was increased from 30 to 50% of total food energy.Most likely, this was because the saturated fatty acidcontent was kept at 10% of energy in both diets. Thetriglyceride concentration decreased as expected with a

reduction in carbohydrate in the diet (25). A decrease intriglyceride might have been expected to increase HDLcholesterol (26); however, this has not been a consistentfinding (2729).

The glucagon area response increased 2.5-fold after theLoBAG diet. This increase is less than the fourfold in-crease that we observed in our previous study (12).However, the difference in fold increase is due, in part, toa difference in the response to the control diets. The netarea response to the three 15% protein meals (control

meals) was less in the previous study compared with thepresent study (139, 127, and 160 vs. 413, 293, and 349 pg h ml1, respectively). Nevertheless, the actual 24-h inte-grated glucagon response also was higher in the currentstudy (893 vs. 525 pg h ml1).

In summary, a LoBAG diet can dramatically reduce the24-h integrated glucose concentration and consequentlythe percentage of glycohemoglobin in people with type 2diabetes. These positive results occur without a significant

change in serum lipids, except for a significant decrease intriacylglycerol concentration.

ACKNOWLEDGMENTS

Thi d d b f h A i

people with untreated non-insulin-dependent diabetes mellitus. Metabo-

lism 45:492 497, 1996

6. Nilsson LH, Furst P, Hultman E: Carbohydrate metabolism of the liver in

normal man under varying dietary conditions. Scand J Clin Lab Invest

32:331337, 1973

7. Atkins RC:Dr. Atkins New Diet Revolution. New York, Avon Books, 19988. Expert Committee on the Diagnosis and Classification of Diabetes Melli-

tus: Report of the Expert Committee on the Diagnosis and Classification of

Diabetes Mellitus. Diabetes Care 21 (Suppl. 11):S5S19, 1998

9. American Heart Association: Dietary guidelines for healthy American

adults: a statement for physicians and health professionals by the Nutrition

Committee.Circulation 74:1465A1468A, 1986

10. US Department of Agriculture:The Food Guide Pyramid. Washington, DC,

U.S. Government Printing Office, 1992

11. US Department of Agriculture, US Department of Health and Human

Services: Nutrition and Your Health: Dietary Guidelines for Americans.

Washington, DC, U.S. Government Printing Office, 1995

12. Gannon MC, Nuttall FQ, Saeed A, Jordan K, Hoover H: An increase in

dietary protein improved the blood glucose response in people with type 2

diabetes.Am J Clin Nutr78:734 741, 2003

13. Rech ME: Observations on the decay of glycated hemoglobin HbA1c

in

diabetic patients. Exp Clin Endocrinol Diabetes 104:102105, 1996

14. Nuttall FQ: A comparison of percent total glycohemoglobin with percent

HbA1c

in people with and without diabetes. Diabetes Care21:14751480, 1998

15. Gannon MC, Nuttall JA, Damberg G, Gupta V, Nuttall FQ: Effect of protein

ingestion on the glucose appearance rate in subjects with type 2 diabetes.

J Clin Endocrinol Metab 86:1040 1047, 2001

16. Bisschop PH, Pereira Arias AM, Ackermans MT, Endert E, Pijl H, Kuipers

F, Meijer AJ, Sauerwein HP, Romijn JA: The effects of carbohydratevariation in isocaloric diets on glycogenolysis and gluconeogenesis in

healthy men. J Clin Endocrinol Metab 85:19631967, 2000

17. Jahoor F, Peters EJ, Wolfe RR: The relationship between gluconeogenic

substrate supply and glucose production in humans. Am J Physiol

258:E288E296, 1990

18. Jenssen T, Nurjhan N, Consoli A, Gerich JE: Failure of substrate-induced

gluconeogenesis to increase overall glucose appearance in normal hu-

mans: demonstration of hepatic autoregulation without a change in plasma

glucose concentration. J Clin Invest 86:489 497, 1990

19. Nuttall FQ, Mooradian AD, Gannon MC, Billington C, Krezowski P: Effect

of protein ingestion on the glucose and insulin response to a standardized

oral glucose load. Diabetes Care 7:465 470, 198420. May JM, Williams RH: The effect of endogenous gastric inhibitory polypep-

tide on glucose-induced insulin secretion in mild diabetes. Diabetes

27:849 855, 1978

21. Gannon MC, Ercan N, Westphal SA, Nuttall FQ: Effect of added fat on the



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E F F E C T O F A H I G H - P R O T E I N ,L O W - C A R B O H Y D R A T E D I E T

O N B L O O D G L U C O S E C O N T R O L

I N P E O P L E W I T H T Y P E 2 D I A B E T E S

P r e s e n t e d B y : L i s t y o n o W a h i d R

M a r y C . G a n n o n A n d F r a n k Q . N u t t a l l

D e p a r t m e n t o f M e d i c i n e , M i n n e s o t a U n i v e r s i t y , M i n n e a p o l i s , 2 0 0 4

Pe m b i m b i n g : d r. A n i t a R a m a d h a n i , S p . P D


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AbstractWe designed a high-protein/low-carbohydrate, weight-main-taining, nonketogenic diet.

We refer to this as a low-biologically-available- glucose

(LoBAG) diet.

Eight men were studied using a randomized 5-week crossover

design with a 5-week washout period.

The carbohydrate : protein : fat ratio of the control diet was

55:15:30. Thetest diet ratio was20:30:50.


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Plasma and urinary-hydroxybutyrate were similar on both diets.

The mean 24-h integrated serum glucose at the end of the

control and LoBAG dietswas 198 and 126 mg/dl.

The percentage of glycohemoglobinwas 9.8 0.5 and 7.6 0.3.

Final calculated glycohemoglobin was estimated to be 6.35.4%.


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Serum insulin was decreased, and plasma glucagon wasincreased. Serum cholesterol was unchanged.

LoBAG diet dramatically reduced the circulating glucose

concentration.

Potentially, this could be a patient empowering way to ameliorate

hyperglycemia without pharmacological intervention.

The long-term effects of such a diet remain to be determined.


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RESEARCH AND DESIGN METHODS

11 Men Mild, Untreated Type 2 DM

Doesnt have :- Hematologic abnormalities

- Kidney disease- Liver disease

- Macroalbuminuria- CHF

- Untreated thyroid disease

Confirmed weight stableat least 3 months

Instructed maintaincurrent activity level

3-day food frequencyquiestionaire

Randomized bya flip of a coin

6 LoBAG 5 Control

3 exclude :Death, Move

Out, NotFinished


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1st day come :

All subject take pre-control and pre-LoBAG diet as

standard meal

2nd day :

All subject take diet

depending on which diet

they were randomizedBlood was

obtained for

24 hours *

Food were sent home

every 2-3 days for 5

weeks

After 5weeks

Overnight

fasting bloodwas drawn

GoHome

Overnightfasting blood

was drawn

All subject take dietdepending on which dietthey were randomized

Blood was obtainedfor 24 hours *

Note :* 1st hour every 15

minutes, 2nd hourevery 30 minutes,

next every hours

Every week bloodwas obtained for

24 hours *


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T ABLE 1 P AT I ENT CHAR ACT ER I ST I CS


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T ABLE 2 COMP OSI T I ON OF DI ET S


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RESULT


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FIG. 1. A: Mean bodyweight while on the

control ( o) or LoBAG ()

diet.

average was 219 10 lb (99 4.5 kg) and 216 10 lb (98 4.5

kg) at the beginning of the control and LoBAG diets.

At the end of 5 weeks, the average on the control diet was 215

10 lb (98 4.5 kg). on the LoBAG diet, 212 9lb (96 4.1 kg).

BODY WEIGHT


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Urine ketones were monitored twice weekly while participants were on the LoBAG diet.

24 hour urine ketones were identical at the beginning and the end of the LoBAG diet

(196 8 and 196 9 mol/l).

Before and after the control diet, they were 187 7 and 203 10 mol/l.

URINE KETONES


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FIG. 1. B: Plasma -hydroxybutyrateconcentration after 5 weeks on the

control ( o) or LoBAG ()diet.

The mean -hydroxybutyrate concentration was 225 15

mol/l after 5 weeks on the control diet on the LoBAG

diet, the mean fasting concentration was 236 27 mol/l.

Beta-hydroxybutyrate


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The mean was 180 10 mg/dl (10 0.6 mmol/l; Fig. 2A). After 5

weeks was decreased to 159 11 mg/dl (8.8 0.6 mmol/l) (P = 0.66).

Control

Plasma Glucose


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LoBAG

Plasma Glucose


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the mean was 167 13 mg/dl (9.3 0.7 mmol/l), after 5 weeks on the LoBAG diet was

significantlydecreased to 119 7 mg/dl (66 0.4 mmol/l) (P < 0.003).

After 5 weeks on the LoBAG diet, the net mean was decreased by 77% (165 59 mg h /

dl) (9.2 3.3 mmol h / l; P


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Control

Serum Insulin


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LoBAG

It was decreased at 5 weeks on the LoBAG diet (318 39 U h

/ ml (1908 702 pmol h./ l). This was a decrease of 40% from

the pre-LoBAG value (P < 0.01). The mean 24-h total integrated

insulin area response decreased by 25%.Serum Insulin


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C-PEPTIDE CONCENTRATIONThe mean before and after the control diet was 0.86 0.08 and 0.91 0.08 pg/ml.

It was 0.81 0.09 and 0.92 0.08 before and after the LoBAG diet (data not shown).

The net C-peptide area response was decreased by 34% after 5 weeks on the LoBAG diet (P < 0.05).


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A decrease in tGHb was present 1 week

after the institution of the LoBAG diet

and became significantby 3 weeks on the

diet. At the end of the 5-week period, the

%tGHb had decreased 22%, from 9.8

0.5 to 7.6 0.3% (P < 0.0007).

Glycohemoglobin


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Control

Plasma Glucagon


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LoBAG

Plasma Glucagon


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The mean were similar before and after both the control and the LoBAG

diets (95 11, 91 8, 91 7, and 94 7 pg/ml. After 5 weeks on the

LoBAG diet, the glucagon response was similar to the control for the first

hour after breakfast. Both the net and the total glucagon area responses were

significantlyincreased after the LoBAG diet (P < 0.05).


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NEFA (Nonesterified Fatty Acid)

The mean NEFA before and after the control and LoBAG diets were 765 67, 654 59, 718 70, and 593

50 Eq/l. These differences were not statistically significant(P > 0.05).

The net area responses were before and after the control and LoBAG diets -5,323 1,187, -2,468 693, -4,525

1,660, and 80 1,809 Eq h / l. The small positive area response after the LoBAG diet was statistically

significantly different compared with the response before the LoBAG diet (P


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Control

Triacylglycerol


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LoBAG

Triacylglycerol


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The mean before and after the control and LoBAG diets were 264 36,

226 32, 246 27, and 149 23 mg/dl.

The concentration was significantlylower after 5 weeks on the LoBAG

diet (P < 0.05).

The net triacylglycerol area response was not significantly different

between diets.

The total area response was significantly lower after 5 weeks on the

LoBAG diet (P < 0.05).


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CHOLESTEROL

The total cholesterol concentrations before and after the control and the LoBAG diets were 195 7, 184 17,

188 10, and 177 8 mg/dl.

The LDL cholesterol before and after the control and the LoBAG diets concentrations were 105 9, 102 2,

105 7, and 110 6 mg/dl

The HDL cholesterol concentrations before and after the control and the LoBAG diets were 38 1, 37 2, 37

2, and 36 2 mg/dl.

Total, LDL, and HDL concentrations were not significantly different between diets or before and after each diet.


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D I S C U S S I O N


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The study was designed to be 5 weeks in duration because 33 days had been reported to be

the half-time for glycohemoglobin to reach a new steady state (13). If this is the point, then the

anticipated final percentage of glycohemoglobin would be 5.4 %.

We previously determined that with the glycohemoglobin method that we use, each 1%

glycohemoglobin represents 20 mg/dl glucose integrated over a 24-h period (14). Using this

information and the 24-h integrated glucose concentration observed at the end of the 5 weeks on the

LoBAG diet, the estimated final percentage of glycohemoglobin would be 6.3%.


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The LoBAG diet resulted in a decrease in 24-h integrated insulin concentration. In our previous

study in which the protein content of the diet was increased from 15 to 30% of total food

energy, the 24-h integrated insulin concentration was slightly increased when compared with

the same control diet used in the present study (12).


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The serum total, LDL, and HDL cholesterol concentrations did not change significantly

when the fat content of the diet was increased from 30 to 50% of total food energy.

Most likely, this was because the saturated fatty acid content was kept at 10% of energy

in both diets. The triglyceride concentration decreased as expected with a reduction in

carbohydrate in the diet (25).


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The glucagon area response increased 2.5-fold after the LoBAG diet. This increase is less than

the four-fold increase that we observed in our previous study (12).

Nevertheless, the actual 24-h integrated glucagon response also was higher in the current study

(893 vs. 525 pg h / ml).


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In summary, a LoBAG diet can dramatically reduce the 24-h integrated glucose concentration

and consequently the percentage of glycohemoglobin in people with type 2 diabetes.

These positive results occur without a significant change in serum lipids, except for a

significant decrease in triacylglycerol concentration.


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