ORIGINAL ARTICLE

Effects of specific medical nutrition on retinal funduschanges in diabetes

Patrizio Tatti • Annabel Barber • Patrizia Di Mauro •

G. Pipicelli • A. Pipicelli

Received: 16 August 2012 / Accepted: 2 January 2013

� Springer-Verlag Italia 2013

Abstract Diabetic retinopathy is a frequent complication

of longstanding diabetes mellitus. While using a special-

ized medical nutrition therapy plus a blend of arginine,

glutamine and b-hydroxy-b-metilbutyrate proven to be

effective to normalize the body composition in diabetics

and improve the rate of healing of the foot ulcers (DFU),

we observed a marked improvement in some markers of

retinopathy progression.

Keywords Diabetic retinopathy � Medical nutrition

therapy � Foot ulcer

Introduction

Diabetic retinopathy (DR) is a frequent and ominous con-

sequence of decompensated diabetes mellitus. The Wis-

consin epidemiologic study of DR demonstrated that 3.6 %

of type 1 diabetics and 1.6 % of type 2 subjects were legally

blind [1], and that after 15 years of disease, the prevalence

of DR may reach 60 % [2]. The results of the United

Kingdom Prospective Diabetes Study (UKPDS), a 10 years

study of newly diagnosed type 2 diabetics, indicate that

using the presence of even one single aneurysm as evidence

of DR the prevalence of this condition at diagnosis is 38 %

[2]. Although the prevalence is higher among type 1 dia-

betics, the much greater absolute number of type 2 diabetes

patients makes DR a true havoc in this condition [3].

From a microscopic viewpoint, it is interesting to notice

that the earliest changes are represented by a damage to the

architecture and cellular composition of the microvascular

structure which is essential to the survival of the retina

[4, 5]. The retinal capillary bed is the structure that allows

the passage of nutrients to the retina and its integrity is

critical to the vision.

Among the structural components of the retinal capillary

most well known are the basement membrane and the

pericyte, a cell that has both structural and regulatory

functions [6]. The disarrangement of these structures leads

to the weakening of the capillary, aneurism formation and

protein leakage. Loss of retinal pericytes represents an

early feature of DR and correlates with microaneurysm

formation [7, 8]. Other common features of early DR are

the thickening of the capillary basement membrane and the

increased deposition of extracellular matrix components.

The subsequent intervention of blood cells that, unfortu-

nately, clog the capillaries and lead to its occlusion is

probably a misguided attempt at damage limitation [9].

Retinopathy is part of a widespread diabetic damage

[10, 11] and the association with foot ulcers (DFU) is

extremely frequent. In a recent study, the prevalence rate of

diabetic retinopathy was almost double in the participants

with foot ulcers in comparison with those without (35 vs.

19 %). In addition, diabetic retinopathy affected 56 % of

patients with neuroischemic foot ulcers [12].

We have recently demonstrated that, in the decompen-

sated diabetic state, there is a loss of the overall cellularity

of the body and of the lean body mass [13]. We have

P. Tatti (&) � P. Di Mauro

Diabetes and Endocrinology Department,

ASL RMH, Rome, Italy

e-mail: tatti0@tin.it

A. Barber

University of Nevada School of Medicine,

Las Vegas, USA

G. Pipicelli � A. Pipicelli

Diabetes and Dietology Unit ASP of Catanzaro,

Catanzaro, Italy

123

Mediterr J Nutr Metab

DOI 10.1007/s12349-013-0120-8

further demonstrated that an adequate medical nutrition

therapy (MNT) plus a blend of arginine, glutamine and b-

hydroxy-b-metilbutyrate (HMB) can reverse these abnor-

malities and markedly increase the rate of healing of the

neuropathic foot ulcers provided that other causal factors

are removed [14–16]. We define this intervention ‘‘poten-

tiated MNT’’ (pMNT). In these subjects, not only the

regrowth of the subcutaneous tissue but also the texture and

the resiliency of the skin are increased due to an increment

in collagen deposition [17]. We hypothesized that this

reconstitution of the tissue should involve other body

structures whose integrity is dependent on the cellularity

and the collagen content. Since the first lesion of diabetic

retinopathy is in the capillary basement membrane, we

decided to look for differences in aneurysm evolution in

subjects treated with pMNT for foot ulcers.

Materials and methods

We followed the evolution of the retinal lesions in 11

insulin treated patients (7 M, 4 F), age 62.6 ± 6.6, with a

diabetic foot ulcer on pMNT with evidence of background

retinopathy, characterized by the presence of microaneu-

rysms (MA) and exudates (E), who came to our hospital

from January 2007 to December 2009. Three of them had

been diagnosed type 1, the other type 2 insulin treated

(Table 1). Their nutritional needs were estimated with the

body impedance analyzer, the level of albumin and other

analytes, and the general physical exam.

The subjects with DFU were started on a MNT tailored

to their needs plus a blend of 7 g of arginine, 7 g of glu-

tamine and 1.2 g of HMB by mouth twice/day in addiction

to any local or systemic antibiotic treatment upon the

diagnosis (pMNT). This treatment was protracted for at

least 1 year to prevent the recurrences of the ulcer. We

used for comparison a matched group of 12 insulin treated

diabetic patients who never used the pMNT, who were in

follow-up for diabetes and background retinopathy. During

this period of observation, we took 8-field color photo-

graphic images of the fundus of the eye with the Topcon

non-mydriatic camera at baseline and at the 6th and 12th

month. It has been shown that fundus photographs are more

reliable than ophthalmoscopy in the diagnosis of diabetic

retinal lesions [18, 19].

We repeated the 8-field fundus photographs of the retina

after 6 and 12 months from the start of the pMNT. We

counted the number of MA and E, both on the screen and

on a color printout of the retina. To improve the accuracy,

we divided the photo in 9 fields with a grid. The number of

microaneurysms per patient reported in the present paper is

the sum of lesions of both eyes.

The data were evaluated with the non-parametric sta-

tistics (Wilcoxon SRT 2-tails) and the SPSS ver. 18 soft-

ware to look for any significant change. Since there was no

randomization in this observational study, we did not make

any statistical intergroup comparison of the number of

microaneurysms and exudates with the controls.

Results

The treated group presented a statistically significant

reduction in the number of microaneurysms and exudates.

After 6 months, the reduction of MA was 19.6 %

(p = 0.016) and after 12 months 37.25 % (p = .008 vs.

the 6th month) (Table 2 and Fig. 1). On the other hand,

there was no reduction in the matched group, rather there

was the expected progression in 10 of 12 and no change in

two (Table 3 and Fig. 1). Table 2 reports the percentage

variation for both groups.

The numbers and the percentage variations of the exu-

dates, both soft and hard, are reported in Table 2. The

reduction in the treated group was statistically significant

(p = 0.004). The exudates were reduced to 35.1 %

(p = 0.002) at 6 months, and to 50.3 % at 12 months

(p = 0.008 vs. the 6th month). We used for comparison a

control group of 12 subjects matched for BMI (30.7 ± 2

vs. 30.28 ± 3.5 km/m2], p = NS), HbA1c (9.2 ± 0.9 vs.

9.1 ± 0.8 %, p = NS), duration of disease (17.6 ± 4

vs. 16.9 ± 6 years, p = NS) and age (62.6 ± 6.6 vs.

64.5 ± 6, p = NS), but not on pMNT. Three of them had

no changes and all the others had an increase in the number

of lesions (Fig. 1).

Comments

We used a tailored MNT plus a blend of arginine, gluta-

mine and HMB (pMNT) for diabetic foot ulcers for more

Table 1 Characteristics of the subjects examined

Age 62.6 ± 6.6 years

Type of diabetes 3 type 1, 8 type 2 insulin treated

Sex 7 males, 4 females

Duration of diabetes 16 ± 8 years

Number of insulin

shots/day

4 subjects: 1/day; 7 subjects C3/day

Other drugs Metformin, sulfanylurea, gliptins, ACE-I,

statins, aspirin

Complications

present

5 subjects, grade I–II nepropathy; 11

peripheral neuropathy, 6 cardiovascular

disease

HbA1c At start 9.9 ± 0.9; after 6 months 8.7 ± 0.6;

after 12 months 7.3 ± 0.6

Mediterr J Nutr Metab

123

than 1 year in 12 insulin treated diabetic subjects with a

diabetic foot ulcer and an initial background retinopathy,

which is a highly frequent event since microvascular dia-

betic complications tend to develop together. As described

elsewhere [14], this medical nutrition considerably short-

ens the time to healing, probably increasing the formation

of collagen and decreasing the inflammatory phenomena.

During this time frame, we followed the evolution of the

retinal lesion with the 8-field color photographic images of

the fundus of the eye obtained with the Topcon non-

mydriatic camera at baseline and at the 6th and 12th month.

The rationale for using microaneurysm counts to further

subdivide Level 20 is based on the observation that the

number of microaneurysms at baseline correlates with the

Table 2 Evolution of the microaneurysms (M) and exudates (E)

Evolution of the microaneurysms Evolution of the exudates

Subjects on pMNT Not on pMNT Subjects on pMNT Not on pMNT

Basal 6 m 12 m Basal 6 m 12 m Basal 6 m 12 m Basal 6 m 12 m

7 5 5 11 12 12 10 7 5 11 10 11

9 9 8 8 12 12 14 7 5 9 11 14

6 5 5 5 7 9 14 12 12 10 7 12

8 8 6 7 16 14 15 8 6 5 7 7

10 9 5 4 9 9 9 7 3 8 9 9

12 8 6 5 7 11 11 7 6 12 12 16

11 7 6 6 12 12 16 7 7 8 11 7

15 10 6 4 4 7 11 7 5 10 11 14

11 10 7 2 8 8 14 8 5 10 8 10

5 4 3 8 10 10 8 7 6 7 7 10

8 7 7 10 10 10 9 8 5 8 9 10

7 7 7 10 10 10

Number of lesions in each subject at baseline and after 6 and 12 months

Fig. 1 Total number of

microaneurysms and exudates.

Treated subjects versus non-

treated with the pMNT

Table 3 Evolution of

retinopathy. Percentage

variation of microaneurysms

and exudates in the treated

subjects

a Non-parametric test

6 months 12 months

Microaneurysmsa

Treated -19.6 % (p = 0.016 vs. baseline) -37.25 % (p = 0.006 vs. 6th month)

Non-treated ?48 % (p = 0.004 vs. baseline) ?57 % (p = 0.005 vs. 6th month)

Exudatesa

Treated -35.1 % (p = 0.002 vs. baseline) -50.38 % (p = 0.008 vs. 6th month)

Non-treated ?3.7 % (p = NS vs. baseline) ?20.4 % (p = NS vs. 6th month)

Mediterr J Nutr Metab

123

severity of the retinopathy [13] and is a significant pre-

dictor of risk of progression to more severe stages of

disease, independent of the glycemic status or type of

diabetes. The fundus camera has been used extensively in

clinical and epidemiological studies of diabetic retinopa-

thy, including the Diabetes Control and Complications

Trial (DCCT) [2, 20] and the UKPDS, to assess baseline

status of retinopathy and progression of disease [2]. The

UKPDS, a 10 years study of newly diagnosed type 2 dia-

betics, used the presence of even a single aneurysm as

evidence of DR [2].

Using this technology, we observed a consistent and

progressive reduction in the number of microaneurysms in

the retina throughout the 12 months of observation. There

was no evidence of reduction of these lesions, rather an

increase, in 10/12 subjects matched for age, BMI and HbA1c

not on this treatment. Although microaneurysms may dis-

appear during the natural course of the disease, this is an

extremely unusual occurrence and, as expected, did not

occur in 12 matched controls not treated with the pMNT. The

presence and the progression of the exudates, both soft and

hard, are not a standardized proxy for the diagnosis, but their

significant statistical reduction is, however, noteworthy and

not unexpected, since these lesions are the by-product of a

leaking capillary basement membrane.

On the basis of this observation, we think that the

ongoing catabolism of the lean body mass caused by the

decompensated diabetic state may have a role in the early

retinal lesions, and that this condition may be at least

partially modified by improving the nutrition of the subject.

The initial retinal damage in diabetes involves the retinal

capillaries with the formation of microaneurysms and

exudates. The anatomical basis of these manifestations is

the disruption of the basement membrane due to a series of

metabolic derangements. The pMNT we used has been able

to help consistently the regeneration of the skin and of the

subcutaneous tissue, increasing the formation of normal

collagen and increasing cellularity and tensile strength of

the tissues. It is thus obvious to surmise that the beneficial

action is also exerted on other tissues, including the cap-

illary basement membrane. We also observed the reduction

of the exudates in the same subject and this also is not

unexpected since the exudates are the by-product of a

leaking capillary basement membrane. The observation

that, in the DCCT on 1,041 type 1 diabetic patients from 29

clinics, the progression of retinopathy appeared to be

related among other variables to the diet [20] adds value to

our results.

There are other studies that demonstrate an improve-

ment in the retinal damage in diabetes with nutritional

interventions. This beneficial action has been explained by

the capacity of the macro and micronutrients to antagonize

the increase in oxidative stress [21, 22] induced by the

persistent hyperglycemia [23]. There are many studies in

the medical literature centered on the effect of individual

dietary components on the retina [24–27] rather than on

nutrition as a whole concept of well being, and none of

these was aimed at the reconstitution of the lean body mass

or of the body cell mass. A more complete review of the

state of the art with these substances can be found in a

recent paper [28].

A limitation of this study is that we did not use any of

the available classification of diabetic retinopathy, that

were, however, created to support the pathological diag-

nosis or the decisions on the treatment, and not to evaluate

the effect of a nutritional supplement on minimal lesions.

In the medical literature, there are, however, many exam-

ples of use of these lesion to evaluate the progression of the

disease [2].

The main limitation of our study is the absence of a

randomized control group, although also randomized

clinical trials by themselves have intrinsic weaknesses too

often overlooked [29–31]. On the basis of our observation,

this should be further confirmed. We can conclude that the

pMNT we used has a beneficial systemic effect and can be

used without any restraint in diabetic patients with neuro-

pathic ulcers. It is highly probable that if these results will

be further confirmed, this treatment may find a role as a

supportive therapy for other microvascular complications

of diabetes.

Conflict of interest None.

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