American Journal of Therapeutics 14, 194–202 (2007)

Metformin Plus Low-Dose Glimeperide Significantly

Improves Homeostasis Model Assessment for
Insulin Resistance (HOMAIR) and b-Cell Function
(HOMAb-cell) Without Hyperinsulinemia in Patients With
Type 2 Diabetes Mellitus

Valmore J. Bermúdez-Pirela, MD,1* Clı́maco Cano, PhD,1 Mayerlim T. Medina, MD,1

Aida Souki, MgSc,1 Miguel A. Lemus, MD,1 Elliuz M. Leal, MD,1 Hamid A. Seyfi, MD,1
Raquel Cano, MD,1 Ana Ciscek, MD,1 Fernando Bermúdez-Arias, MD,1 Freddy Contreras, MD,2
Zafar H. Israili, PhD,3 Rafael Hernández-Hernández, MD,4 and Manuel Valasco, MD2

Objective: Type 2 diabetes mellitus is characterized by insulin resistance and defects in insulin
secretion from pancreatic b-cells, which have been studied by using euglycemic/hyperinsulinemic
clamps. However, it is difficult to study insulin resistance and b-cell failure by these techniques in
humans. Therefore, the aim of this study was to evaluate the effect of three different antidiabetic
therapeutic regimens on insulin resistance and b-cell activity by using a mathematical model,
Homeostasis Model Assessment for insulin resistance (HOMAIR) and b-cell function (HOMAb-cell).
Research design and methods: Seventy type 2 diabetic patients were randomly assigned to one of
three therapeutic regimens: (A) metformin + American Diabetic Association (ADA)–recommended
diet + physical activity; (B) metformin + low-dose glimepiride + ADA diet + physical activity; or (C)
ADA diet + physical activity (no drugs). Blood samples were obtained before and after the treatment
to determine serum levels of fasting and post-prandial blood glucose, fasting insulin, and
glycosylated hemoglobin (HbA1c), and HOMAIR and HOMAb-cell were calculated.
Results: Fasting and post-prandial levels of glucose, HbA1c, and fasting insulin and calculated
HOMAIR and HOMAb-cell values before treatment were significantly higher than the respective
values after treatment for all groups of patients (P , 0.01). Significant differences were also found
when comparing the treatment-induced reduction in fasting blood glucose (51.8%; P , 0.01), post-
prandial blood glucose (55.0%; P , 0.05), and HOMAIR (65.3%; P , 0.01) in patients of Group B with
that in patients receiving other therapeutic options (Groups A and C).
Conclusions: Metformin plus low-dose glimepiride (plus ADA diet and physical activity) is a more
effective treatment for type 2 diabetes than either metformin plus ADA diet and physical activity or
ADA diet and physical activity alone. Determination of HOMAIR and HOMAb-cell values is an
inexpensive, reliable, less invasive, and less labor-intensive method than other tests to estimate
insulin resistance and b-cell function in patients with type 2 diabetes mellitus.

Keywords: type 2 diabetes mellitus, insulin resistance, b-cell function, homeostasis model assessment,
HOMA, metformin, glimeperide

1
Endocrine and Metabolic Diseases Research Center ‘‘Dr. Félix Gómez,’’ University of Zulia School of Medicine, Maracaibo, Venezuela;
2
Unidad de Farmacologı́a Clı́nica, Escuela de Medicina Vargas, La Universidad Central de Venezuela, Caracas, Venezuela; 3Department of
Medicine, Emory University School of Medicine, Atlanta, Georgia, USA; and 4Clinical Pharmacology Unit and Hypertension Clinic, School
of Medicine, Universidad Centroccidental ‘‘Lisandro Alvarado,’’ Barquisimeto, Lara, Venezuela.
*Address for correspondence: Facultad de Medicina, Universidad del Zulia, Final Avenida 20, Maracaibo, Venezuela. E-mail: vbermudez@
hotmail.com

1075-2765 Ó 2007 Lippincott Williams & Wilkins

Oral Anti-diabetic Combined Therapy and HOMA Model
INTRODUCTION
Type 2 diabetes mellitus (DM2) is a frequent endocrine
disease characterized by peripheral insulin resistance,
defects in insulin secretion from the pancreatic b-cells,
and increased hepatic glucose production.1,2 Over the
past 2 decades, several tests have been developed to
evaluate insulin resistance in humans, including the
hyperinsulinemic/euglycemic clamp, the insulin sup-
pression test, the frequently-sampled intravenous glu-
cose tolerance test with computer modeling (FSIGT),
and more recently by measurement of serum levels
of sex hormone–binding globulin.3–10 These methods,
however, are laborious, expensive, and unsuitable for
large-scale studies.5–7 Among the above-mentioned
tests, only FSIGT (through which acute insulin re-
sponse is calculated) and the hyperinsulinemic clamp
can be used to estimate pancreatic insulin secretion
capacity. Because of the inconvenience of these
methods, mathematical models have been developed
to express the metabolic alterations that occur in
DM2.4,8–11
The dynamic interactions between b-cell insulin
secretion and blood glucose concentration and between
muscle-tissue and liver insulin resistance are the main
elements used in the simulation of progression of
DM2.4,5,11,12 However, a mathematical model, the
Homeostasis Model Assessment (HOMA), has been
developed to quantify insulin resistance (HOMAIR)
and b-cell function (HOMAb-cell) with use of only two
input variables: fasting plasma glucose and fasting
plasma insulin.4,12
Recently, the usefulness of HOMAIR as an indicator
of changes in insulin resistance during therapeutic
management of DM2 has been demonstrated by
the reported significant correlation between the
calculated HOMAIR and experimentally determined
insulin resistance with use of a hyperinsulinemic/
euglycemic clamp.13 Such a relationship has also
been demonstrated in studies with sulfonylureas
in DM2 patients.14–17 However, the utility of
HOMAIR and HOMAb-cell to monitor the therapeutic
efficacy of oral antidiabetic drugs in conjunction
with a diet recommended by the American Dia-
betic Association (ADA) and physical activity for
DM2 patients has not been adequately investi-
gated. Therefore, the aim of the present study
was to evaluate the usefulness of HOMAIR and
HOMAb-cell in assessing the efficacy of treatment
with metformin—with or without low-dose glime-
peride with ADA diet and physical activity—and
effects on insulin resistance and b-cell function in
DM2 patients.
195
METHODS
Subject selection
The prospective study was of 70 patients with DM2,
diagnosed according to the ADA criteria,18 who
attended the Centro de Investigaciones Endocrino–
Metabólicas ‘‘Dr. Félix Gómez’’ (School of Medicine,
University of Zulia, Maracaibo, Venezuela). The
selection criteria included an age between 40 and 60
years; duration of DM2 (since diagnosis) of no more
than 10 years; altered metabolic control profile (glyco-
sylated hemoglobin [HbA1c] .8%, fasting glycemia
.126 mg/dL, post-prandial glycemia .140 mg/dL);
and monotherapy with sulfonylureas or a diagnosis of
DM2 without treatment. The study was approved by
the institutional clinical study committee and informed
consent was obtained from all subjects before the
beginning of the study.
Therapeutic intervention
The patients were randomly assigned to one of the
following therapeutic interventions, on the basis of
their exposure to sulfonylureas. Patients who had been
treated previously with sulfonylureas were randomly
assigned to receive one of the two pharmacological
regimens: Group A, metformin 500 mg 3 times daily
(t.i.d.), or Group B, metformin 500 mg t.i.d. +
glimeperide 0.5 mg once a day (q.d.). Subjects without
previous pharmacological therapy were directly as-
signed to the ADA diet and physical activity in-
tervention group (Group C). Group A and B patients
also were assigned the ADA diet and were advised to
engage in physical activity (Table 1). All interventions
continued for 10 weeks.
Metabolic studies
Three fasting venous blood samples were drawn from
all subjects, with a 5-minute interval between collec-
tions, for the measurement of pretreatment fasting
plasma glycemia and basal serum insulin levels. Blood
was processed to obtain plasma and serum. The
average of the 3 values of fasting plasma glucose and
fasting serum insulin was used to calculate the
HOMAIR and HOMAb-cell. Post-prandial (2 hours after
breakfast ingestion) glycemia and HbA1c were also
determined. After this step, the patients were randomly
assigned to the three groups as described above. Each
patient was followed-up weekly for 10 weeks, at which
time the metabolic parameters (fasting glycemia, post-
prandial glycemia, fasting insulin, and HbA1c) were
measured again.
Plasma glucose levels were measured by a colori-
metric enzymatic method (glucose oxidase; HUMAN,
American Journal of Therapeutics (2007) 14(2)
196
Table 1. Characteristics and treatments of patients.
Duration of
Group* Age, years†‡ DM2, years†‡§
A (n = 29) 54.0 6 1.7 5.9 6 0.8
B (n = 21) 49.5 6 1.6 5.3 6 1.1
C (n = 9) 55.3 6 4.9 3.5 6 1.4
*Diabetic patient groups receiving various treatments (see text).
†
mean 6 standard error.
‡
no significant difference between the groups (P . 0.05).
§
duration since diagnosis.
DM2, type 2 diabetes mellitus; t.i.d., three times a day; q.d., once a day.
Germany). Serum insulin was quantitated by using
a solid-phase radioimmunoassay (DPC, USA), and
HbA1c was measured by interchange resin separation
method (Sigma, USA).
Calculation of HOMAIR and HOMAb-cell
Homeostasis model assessment was used to estimate
insulin resistance (HOMAIR) and b-cell function
(HOMAb-cell) by the following formulas:4,12,19 HOMAIR =
[fasting serum insulin (mU/mL)] 3 [fasting plasma
glucose (mmol/L)]/22.5. HOMAb-cell = [20 3 fasting
serum insulin (mU/mL)]/[(fasting plasma glucose–
3.50) mmol/L]. A computer-based HOMA calculator is
available at www.dtu.ox.ac.uk/homa.20
The HOMA values were calculated from insulin and
glucose levels obtained before and after the 10-week
intervention. A normal-weight, healthy person ,35 years
of age has a HOMAIR of 1 and HOMAb-cell of 100%.4
Statistical analysis
All data were processed with the SPSS program
(version 10.0, for Windows; SPSS, Chicago, IL, USA).
Variables that did not fulfill variance normality and
homogeneity required logarithmic transformation in
order to improve the curtosis; still, data are shown in
their original form in figures and tables (without modi-
fication). The differences between means were estab-
lished using either one-way analysis of variance
(ANOVA) or multifactor ANOVA (Tukey’s post-hoc
test) as required. The results were expressed as mean 6
standard error or percentages as reported in the tables
and figures; differences were considered statistically
significant at P , 0.05.
RESULTS
Eleven of the 70 patients enrolled in the study did not
finish the study. Therefore, the data from the remaining
American Journal of Therapeutics (2007) 14(2)
Bermúdez-Pirela et al
Treatment
Physical
Metformin Glimeperide Diet activity
500 mg t.i.d. — Yes Yes
500 mg t.i.d. 0.5 mg q.d. Yes Yes
— — Yes Yes
59 subjects [29 women (49.1%) and 30 men (51.9%)]
were included in the analysis. The final numbers of
participants in the three intervention groups were as
follows: Group A, n = 29 [11 women and 18 men];
Group B, n = 21 [14 women and 7 men]; and Group C,
n = 9 [4 women and 5 men]. There was no significant
difference between groups (Table 1) with respect to age
and the duration of diabetes (since diagnosis).
Fasting and post-prandial blood glucose levels
A statistically significant reduction in fasting glucose
levels was observed (Table 2) when comparing each
group individually before and after the treatment
(Group A: 10.6 6 0.4 mmol/L versus 6.1 6 0.1
mmol/L, P , 0.01; Group B: 13.5 mmol/L 6 0.7 versus
6.0 mmol/L 6 0.1, P , 0.01; Group C: 9.5 mmol/L 6
0.6 versus 6.1 mmol/L 6 0.2, P , 0.01). The percent
reduction in fasting glucose levels by treatment was
the highest (Table 2; Figure 1) in Group B patients
(51.8%), as compared with Group A (40.5%; P , 0.01)
or Group B patients (33.7%; P , 0.01).
There was a statistically significant reduction in
post-prandial glycemia (Table 2) before and after
the treatment (Group A: 12.9 mmol/L 6 0.6 versus
7.1 mmol/L 6 0.3, P , 0.01; Group B: 17.4 mmol/L 6
0.8 versus 7.5 mmol/L 6 0.4, P , 0.01; Group C: 10.9
mmol/L 6 0.9 versus 6.4 mmol/L 6 0.5, P , 0.01).
Intergroup comparisons showed statistically signifi-
cant differences in percent reduction in post-prandial
blood glucose, with the highest reduction (55.0%) in
Group B patients, in comparison with Group A (42.9%;
P , 0.05) and Group C patients (39.8%; P , 0.05) (Table 2;
Figure 1).
Fasting insulin levels
Fasting insulin levels after treatment were significantly
lower (Table 2; Figure 1) than the basal values in all
groups of patients (Group A: 16.3 mUI/mol 6 0.8
versus 12.7 mUI/mol 6 0.6, P , 0.01; Group B: 18.7
Oral Anti-diabetic Combined Therapy and HOMA Model 197

Table 2. Changes in metabolic parameters caused by the three treatments for diabetic patients.

Before treatment* After treatment* Percent change

Group A Group B Group C Group A Group B Group C Group A Group B Group C

Fasting glycemia,
mmol/L 10.6 6 0.4 13.5 6 0.7 9.5 6 0.6 6.1 6 0.1 6.0 6 0.1 6.1 6 0.2 Y40.5† Y51.8† Y33.7†
Post-prandial
glycemia, mmol/L 12.9 6 0.6 17.4 6 0.8 10.9 6 0.9 7.1 6 0.3 7.5 6 0.4 6.4 6 0.5 Y42.9‡ Y55.0‡ Y39.8‡
% HbA1C 10.1 6 0.3 11.5 6 0.6 9.6 6 0.5 6.8 6 0.2 6.9 6 0.3 6.0 6 0.3 Y33.6 Y39.8 Y36.8
Fasting insulin,
mUI/mL 16.3 6 0.8 18.7 6 1.2 14.8 6 1.2 12.7 6 0.6 12.6 6 0.5 11.6 6 0.8 Y22.0 Y27.8 Y20.4
HOMAIR 7.8 6 0.5 11.7 6 1.3 6.4 6 0.8 3.5 60.2 3.4 6 0.1 3.2 6 0.2 Y52.4§ Y65.3§ Y46.9§
HOMAb-cell 49.4 6 3.5 40.0 6 3.1 52.1 6 5.0 103.2 6 6.5 105.8 6 8.5 97.9 6 15.2 Y108.9 Y164.5 Y89.3

The 3 treatments for the diabetic patients were as follows: Group A, metformin 500 mg t.i.d. + ADA diet + physical activity; Group B,
metformin 500 mg t.i.d. + glimeperide 0.5 mg q.d. + ADA diet + physical activity; Group C, ADA diet + physical activity.
*Statistically significant differences within each group P , 0.01.
†
statistically significant difference (P , 0.01) when comparing B with A and C.
‡
statistically significant difference (P , 0.05) when comparing B with A and C.
§
statistically significant difference (P , 0.01) when comparing B with A and C.
ADA, american diabetic association; HOMA, homeostasis model assessment for insulin resistance (HOMAIR) and b-cell function
(HOMAb-cell).

mUI/mol 6 1.2 versus 12.6 mUI/mol 6 0.5, P , 0.01;
Group C: 14.8 mUI/mol 6 1.2 versus 11.6 mUI/mol 6
0.8, P , 0.01). The percent reduction was not
significantly different in any group compared with
the other groups (Table 2).
HbA1C levels
A statistically significant reduction in HbA1C levels
was observed with treatment as compared with the
basal levels (Group A: 10.1 6 0.3% versus 6.8 6 0.2%,
P , 0.01; Group B: 11.5 6 0.6% versus 6.9 6 0.3%,
P , 0.01; Group C: 9.6 6 0.5% versus 6.0 6 0.3%, P ,
0.01). No differences were found in intergroup com-
parisons or percent changes in the HbA1C values (Table
2; Figure 2).
HOMAIR
A statistically significant reduction (Table 2; Figure 2)
was observed when comparing each group before and
after treatment (Group A: 7.8 6 0.5 versus 3.5 6 0.2,
P , 0.01; Group B: 11.7 6 1.3 versus 3.4 6 0.1, P , 0.01;
Group C: 6.4 6 0.8 versus 3.2 6 0.2, P , 0.01). The
percent reduction in HOMAIR values in Group B
patients (65.3%) was significantly higher (P , 0.05)
than the corresponding reduction in either Group A
(52.4%) or Group C patients (46.9%) (Table 2; Figure 2).
HOMAb-Cell
Treatment significantly increased HOMAb-cell values in
all groups (Group A: 49.4 6 3.5 versus 103.2 6 6.5, P ,
0.01; Group B: 40.0 6 3.1 versus 105.8 6 8.5, P , 0.01;
Group C: 52.1 6 5.0 versus 97.9 6 15.2, P , 0.01). The
percent increase in HOMAb-cell values in Group B
patients (164.5%) was higher than the corresponding
increase in either Group A (108.9%) or Group C
patients (89.3%) (Table 2; Figure 2), but the difference
was not significant.
DISCUSSION
A key point in the pharmacological management of
DM2 is to consider the natural evolution of the disease
in order to develop a rational therapeutic approach.
Furthermore, a thorough evaluation of the broad
metabolic changes that occur in patients with DM2
cannot be accomplished simply on the basis of isolated
qualitative or quantitative data, such as determination
of glycemia, as is commonly done in our daily clinical
practice. It is becoming increasingly clear that in
addition to fasting glycemia, other classic parameters
such as HbA1C and post-prandial glycemia and new
parameters such as HOMAIR and HOMAb-cell should
be routinely measured to evaluate patients with DM2
and manage this condition.13–15,21
A number of longitudinal and cross-sectional studies
have conclusively shown that the progression from
normal to impaired glucose tolerance is associated with
the development of severe insulin resistance,22–27
whereas plasma insulin concentrations, both in the
fasting state and in response to a glucose load, are
markedly increased. This phenomenon has been
explained by Randle et al26–30 on the basis of enhanced
American Journal of Therapeutics (2007) 14(2)
198
FIGURE 1. Fasting glycemia, post-prandial glycemia and
fasting insulin treatment (h) and after treatment (n). Group
A: metformin + ADA-diet + physical activity; Group B:
metformin + low-dose glimepiride + ADA-diet + physical
activity; Group C: ADA-diet + physical activity. All intra-group
comparisons were statistically significant (P , 0.01). Inter-
group comparisons for fasting glycemia and postprandial
glycemia were statistically significant as percentages (Group
B verus Group A and C, P , 0.05). See Table 2 for details.
free fatty acid (FFA) oxidation that depletes NAD+
stores (an increase in NADH/NAD+ ratio), leading to
inhibition of the Krebs cycle and a resultant increase in
intracellular levels of citrate and acetyl-CoA. Accumu-
lation of acetyl-CoA and citrate leads to the inhibition
of pyruvate dehydrogenase and phosphofructokinase-1,
American Journal of Therapeutics (2007) 14(2)
Bermúdez-Pirela et al
FIGURE 2. HOMAIR, HOMAb-cell and HbA1c before treat-
ment (h) and after treatment (n). Group A: metformin +
ADA-diet + physical activity; Group B: metformin + low-
dose glimepiride + ADA-diet + physical activity; Group C:
ADA-diet + physical activity. All intra-group comparisons
were statistically significant (P , 0.01). All HOMA IR
inter-group comparisons were statistically significant
as percentages (Group B verus Group A and C, P , 0.01).
See Table 2 for details.
respectively. A consequent rise in glucose-6-phosphate
(G-6-P) levels inhibits hexokinase, which leads to a
reduction in glucose transport via hexosamines path-
way. Finally, decreased glucose transport plus acyl-
CoA glycogen synthase inhibitory effect results in
a drop in glycogen formation. Roden, Shulman, and
Oral Anti-diabetic Combined Therapy and HOMA Model
others31–33 have challenged the biochemical basis of the
Randle cycle on the basis of their studies using a
euglycemic clamp, indirect calorimetry, and nuclear
magnetic resonance (NMR) spectroscopy. These inves-
tigators have shown that free fatty acid (FFA) infusion
in normal subjects inhibited both glycogen synthesis
and glucose oxidation. However, muscle G-6-P con-
centrations (measured by 31P-NMR spectroscopy) also
declined, but the decrease preceded the FFA-mediated
inhibition of glycogen synthesis. In this regard, an
elevation in plasma FFA is the primary defect inhib-
iting glucose transport and phosphorylation, which,
in combination with the decrease in G-6-P (allosteric
activator of glycogen synthase), leads to a reduction in
glycogen synthesis.33,34
These observations provide convincing evidence
that insulin resistance, rather than the impaired insulin
secretion, initiates the process of DM2 in most popu-
lations. Thus, the rationality of the usefulness of
HOMAIR and HOMAb-cell lies in the individual vari-
ability in insulin sensitivity among humans (healthy
or diabetic) as well as the heterogeneous plasma
insulin response to oral glucose stimuli that cause
differences in the therapeutic responses between
patients.35–37 As a matter of fact, ‘‘normal’’ blood
glucose levels are a consequence of a complex
endocrine system in which the outcome variables or
final variables are basal and post-prandial glycemia
and, consequently, HbA1c levels, which depend on
other variables in DM2 patients.38
From a pathophysiological point of view, insulin
resistance and b-cell function can be considered
‘‘incoming’’ variables because they interact with the
biological system prior to the registration of outcome
variables (blood glucose level and HbA1c). Presently,
evaluation of the effectiveness of different thera-
peutic strategies in DM2 patients is performed only
by determination of outcome variables, that is,
measuring the effects and not quantifying the magni-
tude of causes such as insulin resistance and b-cell
failure.6–8,14,17,38 Thus, in the management of patients
with DM2, the quantitation of these variables at diag-
nosis could characterize accurately the disease state
within its natural evolution and therefore provide
guidance for better therapeutic options for such patients.
From all of the points discussed above, many
questions arise: What benefits could be realized from
measuring the incoming metabolic variables in glyce-
mia-regulation systems, at the time of diagnosis and
during follow-up? What would happen if these
variables were considered at the time of establishing
a therapeutic regimen for type 2 diabetic patients?
If the natural evolution of the diabetes is carefully
studied, it can be shown that metabolic alterations
199
related to DM2 begin a decade (or more) before the
development of clinically evident diabetes, with the
progressive development of insulin resistance, usually
as a result of a sustained increase in body mass index,
frequent dietary transgressions, and indeterminate
genetic factors or a combination of all of these. These
factors increase long-chain FFA bioavailability and
generate the initial changes responsible for the decrease
in peripheral insulin sensitivity and the hyperinsuli-
nemic response to insulin resistance.32,33
With an increase in plasma insulin concentrations,
a downregulation of insulin receptors occurs in many
tissues, especially muscle, adipose tissue, brain, liver,
and others, which aggravates the functional metabolic
conditions. A decrease in muscle-tissue response to
insulin leads to fasting and post-prandial hyperglyce-
mia, the characteristic marker of DM2, which becomes
a continuous stimulating factor for insulin secre-
tion.39,40 This process of hyperglycemia-induced in-
crease in insulin release continues until b-cell function
declines.39,40 The combined effect of hyperglycemia
and high plasma FFA leads to b-cell apoptosis via
ceramide metabolism and Fas-receptor upregulation,
which finally results in an irreversible drop in insulin
secretory function of the pancreas.42–44
In the present study, the advantage of combining
low-dose sulfonylurea (glimepiride) with an insulin-
sensitizing agent (metformin) in the metabolic control
of diabetes can be seen by the observations that the
reductions in both the fasting blood glucose and post-
prandial glycemia in patients in Group B (metformin +
glimepiride + diet + physical activity) were signifi-
cantly higher than those in Groups C and B (P , 0.01).
However, the decrease in HbA1c values (33.6% to
39.8%) in the three groups of patients was similar,
although one would expect that Group B patients with
superior metabolic control would have lower HbA1c
values than patients in Groups A and C. This may be
due to the fact that the study was too short (10 weeks)
to exhibit significant differences in HbA1c values
between the three treatments; long-term treatment, as
being conducted now, may reveal such differences.
This study, using the HOMA mathematical models,
confirms the results of a previous investigation39
carried out in a smaller group of patients with use of
a hyperinsulinemic pump and minimal model (Min-
Mod) analysis: the majority of diabetic patients at the
time of diagnosis have some failure in global b-cell
function. In the present study, the fasting insulin levels
in diabetics were normal, but the global b-cell function
was reduced (a decrease of 40% to 52% in functional
capacity in all patients before treatment). Therefore,
this mathematical model is able to identify and
quantitate global changes in b-cell function, beyond
American Journal of Therapeutics (2007) 14(2)
200
the usual 2-hour post-prandial period and abnormal
insulin secretion pattern.
Another important finding in this study is that
b-cell function improved to about 100% with diet
and physical activity, with or without pharmacother-
apy, suggesting that in the early stages of diabetes
evolution, insulin production and secretion can recover
by the following of a strict dietary and physical activity
regimen alone. But the improvement in insulin re-
sistance was much more with the addition of low-dose
sulfonylurea to the treatment regimen than without it.
This may be due to a modest peripheral sensitizing
effect of low-dose glimepiride, in addition to its effect
on the K+/ATP-sensitive channel blockade in the
b cells. It is likely that normal to high doses of sulfo-
nylureas produce hyperinsulinemia and consequently
cause insulin-receptor downregulation, leading to high-
er insulin resistance. Thus, we propose that metformin,
used as a tissue-sensitizing agent, notably decreases
the hyperglycemic and lipotoxic stress suffered by the
b-cell, allowing it to rapidly recover its function, as
shown by HOMAb-cell values determined before and
after metformin treatment. The addition of low-dose
sulfonylurea (glimepiride) does not induce b-cell
hyperfunction and the resultant hyperinsulinemia,
as shown by HOMAb-cell determination.
It can be concluded that all patients studied had
a moderate degree of insulin resistance at the beginning
of this study (HOMAIR values of 6.4 to 11.7) and that
there was substantial improvement in this parameter
with any of the three treatment options employed.
However, it must be appreciated that the percent
decrease in insulin resistance was the highest with the
combination of glimepiride with metformin. This is an
interesting finding, because metformin was the only
insulin-sensitizing drug used in the study; therefore, it
may be proposed that this beneficial effect may have
resulted from a remarkable peripheral sensitizing effect
of sulfonylurea at low doses, causing a ‘‘downregulation
escape of the insulin receptors.’’ The latter situation is
not observed at the usual doses of sulfonylureas, which
are 100% to 400% higher (1–4 mg/day of glimepiride)
than used in the present study, although one may
expect that the higher doses of sulfonylurea would have
a greater effect on pancreatic function (HOMAb-cell $
100%). Therefore, it can be implied that the majority of
individuals treated exclusively with this drug group
(sulfonylurea) would exhibit one of the two unwanted
effects: unrestrained hyperinsulinemia and insulin
receptor downregulation or a b-cell function failure.
In light of all this evidence, taken together, it may
be surmised that early pharmacological intervention
with drug combinations, such as used in this study,
may improve metabolic parameters as well as overall
American Journal of Therapeutics (2007) 14(2)
Bermúdez-Pirela et al
control of the disease. More studies are needed to
determine whether early pharmacological intervention
with a combination of oral agents improves b-cell
function and prevents long-term b-cell failure, thus
avoiding the need for insulin in the long-term control
of diabetes.
In conclusion, the HOMAIR and HOMAb-cell math-
ematical models are reliable and practical techniques to
estimate insulin resistance and b-cell function, re-
spectively, in patients with DM2. Although the HOMA
models are inexpensive, reliable, less invasive, and less
labor-intensive than other tests for estimating insulin
resistance and b-cell function, there are certain
limitations for their application, such as in DM2
patients with low body mass index, low b-cell function,
and high fasting plasma glucose who have insulin
secretory defects.45 It is noteworthy that all 3 thera-
peutic strategies used in this study (pharmacotherapy
with metformin, with or without low-dose glimepiride
and/or diet and physical activity) were effective in
achieving good metabolic control in DM2 patients.
However, the addition of low-dose glimepiride to the
therapeutic regimen proved to be much superior to
regimens without the sulfonylurea in improving meta-
bolic control, especially insulin resistance and b-cell
secretory capacity, as determined by HOMA. Our
results also suggest that the b-cell secretory function
fatigue is a reversible phenomenon, at least during the
early years of progression of diabetes. The use in daily
clinical practice of mathematical (HOMA) models to
monitor the effectiveness of therapy in type 2 diabetic
patients, by estimating insulin resistance and b-cell
function at the time of diagnosis as well as during
follow-up, is highly recommended.
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