Invest Clin 65(3): 358 - 368, 2024 https://doi.org/10.54817/IC.v65n3a08

Corresponding author: Fengnian Guo, Department of Endocrinology, South of Guang’anmen Hospital, China Aca-

demy of Chinese Medical Sciences, Beijing, 102618, China. E-mail: leidui26492806@163.com

Impact of a ketogenic diet on intestinal

microbiota, cardiometabolic, and glycemic

control parameters in patients with Type 2

diabetes mellitus.

Na Lu

, Xincui Zhou

and Fengnian Guo

Department of Colorectal Surgery, South of Guang’anmen Hospital, China Academy

of Chinese Medical Sciences, Beijing, China.

Department of Endocrinology, South of Guang’anmen Hospital, China Academy

of Chinese Medical Sciences, Beijing, China.

Keywords: ketogenic diet; Type 2 diabetes mellitus; intestinal flora; glucagon like

peptide-1; glycosylated hemoglobin.

Abstract. A ketogenic diet (KD), characterized by high fat and low carbo-

hydrate intake, has been proposed as a therapeutic option for Type 2 Diabetes

Mellitus (T2DM). One hundred individuals with T2DM were selected and divid-

ed into a control group (CG) and an observation (OG) group, with 50 patients

in each group, to investigate the effects of a KD on the intestinal flora, Gluca-

gon Like Peptide-1 (GLP-1), and HbA1c levels in T2DM patients. Individuals in

the CG were given standard treatment and diet, while patients in the OG were

given a KD based on the CG. The blood glucose index, blood lipid index, HbA1c,

GLP-1 levels, physical examination, and intestinal flora were compared in both

groups. The FPG, HbA1c, two h PG, HOMA-IR TG, TC, and LDL-C levels in the

two groups were reduced when compared to those before treatment (p<0.05),

and the decreases in the OG were more significant than in the CG (p<0.05),

while the levels of GLP-1 in the two groups were increased compared to those

before treatment, those in the OG were significantly increased when compared

to the CG (p<0.05). After treatment, waist circumference, BMI, body mass,

and the levels of Enterococcus faecalis (E. faecalis) and Escherichia coli (E.

coli) of the two groups were reduced compared to indicators before treatment

(p<0.05), and those in the OG were even lower than those in the CG (p<0.05).

In conclusion, these findings underscore the KD’s potential to act as an effica-

cious dietary strategy in managing T2DM.

Effects of a ketogenic diet in patients with T2DM 359

Vol. 65(3): 358 - 368, 2024

Impacto de una dieta cetogénica en la microbiota intestinal

y los parámetros de control cardiometabólico y glucémico

en pacientes con diabetes mellitus tipo 2.

Invest Clin 2024; 65 (3): 358 – 368

Palabras clave: dieta cetogénica; diabetes mellitus tipo 2; flora intestinal; péptido-1

similar al glucagón; hemoglobina glicosilada.

Resumen. Una dieta cetogénica (KD), caracterizada por una ingesta alta

en grasas y baja en carbohidratos, se ha propuesto como una opción terapéuti-

ca para la diabetes mellitus tipo 2 (DM2). Se seleccionaron cien individuos con

DM2 y se dividieron en un grupo control (GC) y un grupo de observación (GO),

con 50 pacientes en cada grupo, para investigar los efectos de una dieta ceto-

génica sobre los niveles de la flora intestinal, el péptido similar al glucagón-1

(GLP-1) y la HbA1c en pacientes con DM2. Los individuos del GC recibieron tra-

tamiento y dieta estándar, mientras que los pacientes del GO recibieron el tra-

tamiento estándar similar al GC, más una dieta cetogénica. En ambos grupos

se compararon el índice de glicemia, el índice de lípidos en sangre, la HbA1c,

los niveles del GLP-1, el examen físico y la flora intestinal. Los niveles de FPG,

HbA1c, 2h PG, HOMA-IR TG, TC y LDL-C en los dos grupos se redujeron en

comparación con los de antes del tratamiento (p<0,05), y las disminuciones en

el GO fueron más significativas que en el grupo GC (p<0,05), mientras que los

niveles de GLP-1 en los dos grupos aumentaron en comparación con los de an-

tes del tratamiento, los del GO aumentaron significativamente en comparación

con el GC (p<0,05). Después del tratamiento, la circunferencia de la cintura,

el IMC, la masa corporal y los niveles de Enterococcus faecalis (E. faecalis) y

Escherichia coli (E. coli) de los dos grupos se redujeron en comparación con

los indicadores antes del tratamiento (p<0,05), y los del GO fueron incluso

más bajos que los del GC. (p<0,05). En conclusión, estos hallazgos subrayan

el potencial de la KD para actuar como una estrategia dietética eficaz en el

tratamiento de la DM2.

Received: 03-03-2024 Accepted: 13-05-2024

INTRODUCTION

Type 2 Diabetes Mellitus (T2DM) is a

chronic metabolic disorder marked by ele-

vated blood sugar levels

. T2DM is linked to

metabolic syndrome and insulin resistance.

It is influenced by genetics, obesity, inactiv-

ity, and ethnicity

2, 3

. The prevalence of T2DM

varies globally, with a higher incidence in

developed countries. As per the most re-

cent report from the International Diabetes

Federation (IDF), the worldwide incidence

of T2DM among adults stood at 536.6 mil-

lion individuals (10.5%) in 2021. It is pro-

jected that the number of individuals living

with diabetes will reach 783.2 million people

(12.2%) globally by the year 2045

From a pathophysiological perspective,

T2DM is associated with insulin resistance,

wherein the body’s cells are less responsive

to insulin, and a gradual failure of pancre-

atic β-cells to compensate for this increased

360 Lu et al.

Investigación Clínica 65(3): 2024

demand

. This dysfunction is reflected in

the hallmark signs and symptoms of T2DM,

which include polyuria, polydipsia, polypha-

gia, and weight loss

Long-term complications of T2DM are

broad-ranging and include microvascular

damage leading to retinopathy, neuropathy,

and nephropathy, as well as macrovascular

complications such as coronary artery dis-

ease, peripheral arterial disease, and cere-

brovascular disease

7, 8

Diagnosis of T2DM is typically con-

firmed through several tests, including fast-

ing plasma glucose (FPG), 2-hour plasma

glucose (2-h PG) during an oral glucose

tolerance test (OGTT), and hemoglobin

A1c (HbA1c) levels, which reflect the mean

blood glucose levels over the previous two to

three months

Treatment modalities for T2DM include

lifestyle interventions, oral hypoglycemic

agents, non-insulin injectables, and insulin

therapy

10, 11

. Among the dietary strategies,

the KD (a high-fat, adequate-protein, low-

carbohydrate diet) has emerged as a poten-

tial therapeutic option

12, 13

. This diet aims to

induce a state of ketosis, where the body uti-

lizes fat as a primary energy source instead

of glucose

The KD has been associated with al-

terations in the gut microbiota, which play

a crucial role in metabolic health

. A shift

in intestinal flora could potentially influ-

ence the incretin hormone glucagon-like

peptide-1 (GLP-1), which promotes insulin

secretion and improves glycemic control.

Furthermore, the KD could influence HbA1c

levels, providing a broader metabolic benefit

for patients with T2DM

16,17

However, the literature presents a pau-

city of comprehensive studies that holisti-

cally examine the effects of a KD on both the

intestinal microbiota and the serum levels

of GLP-1 and HbA1c in patients with T2DM.

Therefore, this study aims to explore the ef-

fects of a KD on intestinal flora and serum

GLP-1 and glycosylated hemoglobin levels in

T2DM patients.

PATIENTS AND METHODS

This study was conducted as an inter-

ventional study with a randomized controlled

trial (RCT) design. The study spanned over

six months, from June 2021 to June 2022, at

the South of Guang’anmen Hospital.

Based on the random number table

method, 100 T2DM patients were selected

and divided into a control group (CG) and

an observation group (OG), with 50 patients

in each group. As shown in Table 1, there

were no significant differences between the

two groups in general data (P>0.05).

Our hospital’s Ethics Committee re-

viewed and approved the study, and patients

signed the informed consent form.

Inclusion criteria: ① Patients with

T2DM were initially diagnosed through clini-

cal signs and symptoms (polyuria, polydipsia,

polyphagia, unexplained weight loss, fatigue,

Table 1

Clinical data of patients.

Group n

Sex(n)

Age x ± SD BMI (kg/m

) x ± SD

Male Female

CG 50 31 19 53.11±9.69 27.32±5.23

OG 50 32 18 52.64±10.53 27.06±5.56

t/χ² 0.043 0.232 0.241

p 0.836 0.817 0.810

CG: Control group, OG: Observation group, x ± SD: mean ± standard deviation (SD), BMI: Body mass index, t:

t-test, χ²: chi-square test.

Effects of a ketogenic diet in patients with T2DM 361

Vol. 65(3): 358 - 368, 2024

and blurred vision), and serological indica-

tors (FPG >7.0 mmol/L or 126 mg/dL; a

plasma glucose concentration equal to or

exceeding ≥11.1 mmol/L or 200 mg/dL two

hours after a 75-g oral glucose tolerance test

(OGTT); HbA1c >6.5% or higher was also in-

dicative of T2DM)

18, 19

, ② Patients with good

treatment compliance; ③Complete and ac-

curate medical records.

Exclusion criteria: ① Patients with oth-

er serious diabetic complications such as ke-

toacidosis; ② Patients with other endocrine

diseases; ③ Heart, liver, and kidney failure

patients; ④ Patients with drug allergy epi-

sodes in the past.

The patients in the CG were given stan-

dard treatment: patients were instructed to

control their diet, exercise appropriately,

quit smoking, and limit alcohol consump-

tion, and blood glucose was closely moni-

tored. Patients in the OG were given a KD

based on treatment in the CG. High-protein

and low-carbohydrate KD treatment includ-

ed 1/5-2/5 of fat, 2/5 of protein, 1/5 of car-

bohydrate, keeping regular three meals. This

diet limits carbohydrate intake to around

20-50 grams daily and increases fats such as

meat, fish, eggs, nuts, and healthy oils. On

the other hand, adjusting protein consump-

tion is also part of this diet; if much protein

is consumed, it can be converted to glucose

and may slow the transition to ketosis. The

intake of fat was rich in ω-3 mainly, such as

sardines, salmon, tuna, and other sources of

this fat. The amount of drinking water was

more than 2000 mL/d, multiple mineral vi-

tamins needed to be supplemented, and the

amount of exercise remained at the previous

level. Both groups of patients were treated

continuously for six months.

Serological indicators

The two groups of patients had 5 mL of

fasting peripheral venous blood collected in

the morning before and after treatment, cen-

trifuged at 3000 r/min, and the supernatant

stored at 4°C. A radioimmunoassay was used

to measure fasting blood glucose (FPG) and

postprandial blood glucose (2h PG), ELISA

was used to detect fasting insulin (FINS),

and an insulin resistance index was used

to determine insulin resistance (HOMA-

IR=(FPG×FINS)/22.5. All the kits were pro-

vided by the Shanghai Enzyme Linked Bio-

technology Co., Ltd. and operated strictly

according to the specifications of the kit

instructions. The levels of triglycerides (TG)

and total cholesterol (TC) were detected by

ELISA, and the levels of low-density lipopro-

tein cholesterol (LDL-C) were detected by

the surfactant clearance method. ELISA de-

tected serum HbA1c and GLP-1 levels.

Physical examination indicators

Intestinal flora

Before and after treatment, 0.1g of fresh

feces from the two groups of patients were

collected, mixed with normal saline, and in-

oculated into the culture medium containing

aerobic and anaerobic bacteria, respectively.

The aerobic bacteria mainly refer to bifido-

bacteria and lactobacillus. The culture envi-

ronment was aerobic; the temperature was

set at 37°C, and the time was 48h. Anaerobic

bacteria refer to E. faecalis and E. coli. The

air extraction and ventilation method was

adopted, and the incubation time was 72h.

After the culture, the BIOLOG automatic

microbial identification system detected the

Bifidobacterium, Lactobacillus, Fecal Entero-

coccus, and E. coli levels.

Statistical methods

IBM SPSS 20.0® was used for statisti-

cal analysis, and the counting data were χ

The measurement data were expressed by

mean ± standard deviation (Mean±SD) and

compared by the t-test. The difference was

statistically significant when p<0.05

RESULTS

Blood glucose indicators in each group

There was no difference (p>0.05) in

blood glucose between the two groups be-

fore treatment. After treatment, the levels

362 Lu et al.

Investigación Clínica 65(3): 2024

of FPG, 2h PG, and HOMA-IR in both groups

were reduced compared to those before

treatment (p<0.05), and those in the OG

were even more reduced than those in the

CG (p<0.05), as shown in Table 2.

Blood lipid indexes in each group

Blood lipid indexes between the two

groups were no different before treatment

(p>0.05). After treatment, the levels of TG,

TC, and LDL-C in the two groups were re-

duced compared to those before treatment

(p<0.05), and the levels in the OG were

even more reduced than those in the CG

(p<0.05) (Table 3).

HbA1c and GLP-1 levels in each group

Before treatment, HbA1c and GLP-1 lev-

els between the two groups were no different

(p>0.05); after treatment, those in the two

groups were raised compared to those before

treatment, and the levels of HbA1c in the CG

were higher than those in the OG (p<0.05).

The concentration of GLP-1 in the OG was

higher than in the CG after six months of

treatment (p<0.05), as shown in Table 4.

Physical examination indexes in each

group

Before treatment, the two groups’ waist

circumference, BMI, and body mass were no

different (p>0.05). After treatment, waist

circumference, BMI, and body mass of the

two groups were reduced compared to those

before treatment, and the indicators of the

OG were even more reduced than in the CG

(p<0.05) (Table 5).

Comparison of intestinal flora in each

group

Before treatment, the intestinal flora

between the two groups was no different

Table 2

Blood glucose indicators in each group before and after six months of treatment.

Group N

FPG (mmol/L) 2h PG (mmol/L) HOMA-IR

Before After Before After Before After

CG 50 8.45±1.24 7.29±0.98

13.01±1.72 10.22±1.47

3.86±0.72 2.87±0.55

OG 50 8.32±1.07 6.57±1.01

12.83±1.66 8.63±1.25

3.77±0.67 2.43±0.48

t 0.561 3.618 0.533 5.827 0.647 4.262

p 0.576 0.000 0.596 0.000 0.519 0.000

CG: Control group, OG: Observation Group, FPG: Fasting Plasma Glucose, 2h PG: 2-hour Postprandial Glucose,

HOMA-IR: Homeostatic Model Assessment of Insulin Resistance, t: t-test, values are expressed as Mean±SD *:

p<0.05 compared with the patients in this group before treatment.

Table 3

Blood lipid indexes in each group before and after six months of treatment.

Group N

TG TC LDL-C

Before After Before Before Before After

CG 50 2.57±0.61 1.97±0.42

5.23±0.96 4.41±0.91 3.69±1.02 3.01±0.76

OG 50 2.53±0.57 1.62±0.38

5.21±1.13 3.94±0.77 3.63±0.95 2.65±0.41

t 0.339 4.370 0.095 2.788 0.304 2.948

p 0.736 0.000 0.924 0.006 0.762 0.004

CG: Control group, OG: Observation group, TG: triglyceride, TC: total cholesterol, LDL-C: low-density lipoprotein

cholesterol. Values are expressed as mmol/L. t: t-test, *: p<0.05 compared with the patients in this group before

treatment, * p<0.05.

Effects of a ketogenic diet in patients with T2DM 363

Vol. 65(3): 358 - 368, 2024

(p>0.05). After treatment, the levels of Bi-

fidobacterium and Lactobacillus in the two

groups were increased compared to those

before treatment, and those in the OG were

higher than in the CG (p<0.05). After treat-

ment, the levels of E. faecalis and E. coli in

the two groups were reduced to those before

treatment (P<0.05), and the levels in the

OG were even lower than those in the CG

(p<0.05) (Table 6).

DISCUSSION

The ketogenic diet (KD) has been in-

creasingly studied for its potential therapeu-

tic effects in various health conditions, in-

cluding type 2 diabetes mellitus (T2DM)

T2DM is a chronic condition characterized

by insulin resistance and impaired glucose

metabolism

. This study aimed to investi-

gate the impact of a KD on the intestinal

Table 4

HbA1c and GLP-1 levels in each group before and after six months of treatment.

Group N

HbA1c (%) GLP-1 (μ mol/L)

Before After Before After

CG 50 8.41±1.12 7.51±1.09* 6.72±0.88 11.34±1.11*

OG 50 8.53±1.18 6.64±0.87* 6.64±0.52 14.43±2.28*

t 0.522 -4.411 -0.553 8.616

p 0.603 0.000 0.581 0.000

CG: Control group, OG: Observation group, HbA1c: hemoglobin A1c, GLP-1: glucagon-like peptide 1, t: t-test, *

p<0.05 compared with the patients in this group before treatment.

Table 5

Physical examination indexes in each group before and after six months of treatment.

Group N

Weight (kg) BMI (kg/m

) Waist circumference (cm)

Before After Before After Before After

CG 50 90.02±10.80 72.14±9.63

30.58±2.81 25.70±1.42

98.63±3.41 86.84±3.25

OG 50 89.12±10.72 67.76±9.58

30.46±2.92 24.25±1.35

98.56±3.35 80.62±2.20

t -0.418 -2.280 -0.209 -5.233 -0.104 -11.207

p 0.677 0.025 0.835 0.000 0.918 0.000

CG: Control group, OG: Observation group, BMI: body mass index, t: t-test, *: p<0.05 compared with the patients

in this group before treatment.

Table 6

Intestinal flora in each group before and after six months of treatment.

Group N

Bifidobacterium Lactobacillus E. faecalis E. coli

Before After Before After Before After Before After

CG 50 7.54±0.95 8.15±0.86

6.93±0.99 7.58±0.82

8.22±0.83 7.42±0.72

9.46±1.15 8.16±1.18

OG 50 7.62±1.14 8.82±0.76

6.84±0.92 8.12±0.93

8.16±0.76 6.56±0.77

9.64±1.23 7.24±0.87

t 0.381 4.128 -0.471 3.080 -0.377 -5.769 0.756 -4.437

p 0.704 0.000 0.639 0.003 0.707 0.000 0.452 0.000

CG: Control group, OG: Observation group. Values are expressed as lgCFU/g, t: t-test, *: p<0.05 compared with

the patients in this group before treatment.

364 Lu et al.

Investigación Clínica 65(3): 2024

microbiota and the serum levels of gluca-

gon-like peptide-1 (GLP-1) and glycosylated

hemoglobin (HbA1c) in patients with T2DM.

The present study’s findings suggest

that patients with T2DM who followed a KD

for six months exhibited significant improve-

ments in their serum levels of GLP-1 and

HbA1c, as well as their blood glucose and

lipid profiles, compared to the control group

receiving standard treatment. Additionally,

there were notable changes in the composi-

tion of the intestinal microbiota, with an in-

crease in beneficial bacteria such as Bifido-

bacterium and Lactobacillus, and a decrease

in potentially harmful bacteria like E. faeca-

lis and E. coli.

Several studies have investigated the

impact of a KD on weight, blood glucose lev-

els, and lipid profiles in patients with T2DM.

In line with the present study, the research

findings suggest that a KD can induce posi-

tive changes in these parameters, offering

potential benefits for managing T2DM. Li

et al.’s study results show that following a

KD can lead to a decrease in fasting blood

glucose and glycosylated hemoglobin levels

in T2DM patients, which indicates an im-

provement in blood glucose management

Zhou et al.

also conducted a meta-analysis

to investigate the role of KD in controlling

body weight and managing blood sugar in

overweight patients with T2DM. The results

show that the KD significantly reduces body

weight, reduces waist circumference, reduc-

es glycosylated hemoglobin and triglycer-

ides, and increases high-density lipoproteins

(HDL)

Additionally, the improvement in lipid

profiles, particularly the reduction in triglyc-

eride levels, is corroborated by Yuan et al.

The KD’s impact on lipid profiles, especially

triglyceride levels, is likely due to its effects

on insulin secretion and lipid metabolism. By

reducing carbohydrate intake and increasing

fat intake, the diet leads to a decrease in insu-

lin secretion, which in turn reduces the con-

version of excess carbohydrates into triglyc-

erides in the liver

. Additionally, the diet’s

high-fat content provides a source of energy

that is less likely to be stored as triglycerides

in adipose tissue, further contributing to the

reduction in triglyceride levels

The efficacy of insulin action is ensured

through a cellular signalling cascade, which

encompasses membrane insulin receptors

(IRS) and intracellular proteins (PI3K and

AKT). Critical for the uptake of plasma

glucose into tissues, these interactions be-

tween proteins play a vital role. Conversely,

deficiencies in cellular signal transduction

and insulin responses to insulin stimulation

(IR) can disrupt glucose regulation, conse-

quently contributing to the onset of T2DM

. The reduction in carbohydrate intake in

a KD induces a state of nutritional ketosis,

which alters the body’s metabolism, leading

to improved blood glucose levels and insu-

lin sensitivity

28, 29

. In line with the present

study, a systematic study by Huang et al. re-

vealed that the ketogenic diet can improve

insulin sensitivity in individuals with type

2 diabetes, with the most significant effect

resulting from a ketogenic diet paired with

exercise

. The study by Paoli et al. also con-

firms these findings and states that a keto-

genic diet can improve blood sugar control

and insulin sensitivity

The reduction in HbA1c levels in the

observation group supports the results of

a study by Rafiullah et al., which concluded

that very low-carbohydrate ketogenic di-

ets effectively reduce HbA1c in individuals

with T2DM

. A recent systematic review

and meta-analysis conducted by Zaki et al.

found that low carbohydrate (LCD) and KD

positively impact glucose regulation in indi-

viduals with Type 2 Diabetes. Nevertheless,

the analysis indicated that ketogenic diets

demonstrate notably higher effectiveness in

lowering HbA1c levels (− 1.45%) when com-

pared to LCD (− 0.27%)

The results of the present study showed

that the ketogenic diet increases the serum

level of GLP-1 in diabetic patients. GLP-1 is

a hormone produced by the intestines that

helps regulate blood sugar levels and stimu-

Effects of a ketogenic diet in patients with T2DM 365

Vol. 65(3): 358 - 368, 2024

lates insulin secretion

. Widiatmaja et al.

conducted a study to analyze the long-term

effect of KD on the serum levels of adipo-

nectin and IGF-1 in rats. The results showed

that long-term KD increases serum adipo-

nectin levels and does not affect serum IGF-

1 levels

. This finding is contrary to the

results of the present study, which could be

due to the type of participants and the type

of study. Since human studies on this param-

eter have not been conducted in people with

a KD diet, it is necessary to investigate this

matter further.

Finally, the present study showed that

KD improves intestinal microbiota. KD im-

proves Bifidobacterium and Lactobacillus lev-

els and reduces E. faecalis and E. coli levels

in the intestine. Previous studies have also

shown that a very low-calorie ketogenic diet

(VLCKD) can lead to significant changes in

gut microbiota composition in drug-naïve

patients with T2DM and obesity. One study

compared the effects of VLCKD and a hypo-

caloric Mediterranean diet (MD) on gut mi-

crobiota in patients with T2DM and obesity.

The results showed that the VLCKD group

had more significant changes in gut micro-

biota composition

. The study of Paoli et al.

also supports this idea and results

. Since

the number of studies in this field is limited,

more studies are recommended.

In conclusion, this study confirms that

a ketogenic diet significantly outperforms

standard dietary treatments for type 2 diabe-

tes mellitus over six months. It more effec-

tively lowers blood glucose levels, improves

lipid profiles, reduces body weight and waist

circumference, and beneficially alters gut

microbiota. These findings highlight the ke-

togenic diet’s potential as a superior dietary

intervention for managing type 2 diabetes.

Authors’ ORCID number

• Na Lu: 0000-0001-5222-6675

• Xincui Zhou: 0009-0000-5661-531X

• Fengnian Guo: 0009-0008-8713-8833

Contributions of authors

All authors were involved in data collec-

tion, article design, interpretation of results,

review, and manuscript preparation.

Conflict of interests

The authors declare no conflict of interest.

Funding

None.

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