East African Medical Journal Vol. 85 No. 1 January 2008TYPE 2 DIABETES MELLITUS: CLINICAL AND AETIOLOGIC TYPES, THERAPY AND QUALITY OF GLYCAEMICCONTROL OF AMBULATORY PATIENTSC. F. Otieno, MBChB, MMed, Senior Lecturer, Department of Clinical Medicine and Therapeutics, A. N. Huho, MBChB,MMed, Department of Clinical Chemistry, E. O. Omonge, MBChB, MMed, Lecturer, Department of Clinical Medicineand Therapeutics, A. A. Amayo, MBChB, MMed, Department of Clinical Chemistry and E. Njagi, MBChB, MSc(Immunology), Lecturer, Department of Immunology, College of Health Sciences, University of Nairobi, P. O. Box 19676-00202, Nairobi, Kenya
Request for reprints to: Dr. C.F. Otieno, Department of Clinical Medicine and Therapeutics, College of Health Sciences,University of Nairobi, P. O. Box 19676-00202, Nairobi, Kenya
TYPE 2 DIABETES MELLITUS: CLINICAL AND AETIOLOGIC TYPES, THERAPY AND QUALITY OF GLYCAEMIC CONTROL OF AMBULATORY PATIENTS
C. F. OTIENO, A. N. HUHO, E. O. OMONGE, A. A. AMAYO and E. NJAGI
ABSTRACT Background: Type 2 diabetes is a heterogeneous disease with multiple causes revolving around beta cell dysfunction, insulin resistance and enhanced hepatic glucose output. Clinical judgement based on obesity status, age of onset and the clinical perception of residual beta cell insulin secretory function (hence insulin-requiring or not), has been used to determine therapeutic choices for each patient. Further laboratory testing of the clinically defined type 2 diabetes unmasks the various aetiologic types within the single clinical group. Objective: To determine the aetiological types of the clinically defined type 2 diabetic patients, their chosen therapies at recruitment and the quality of glycaemic control achieved. Design: Descriptive cross-sectional study. Setting: Diabetes out-patient clinic of Kenyatta National Hospital, Nairobi, Kenya. Results: A total of 124 patients with clinical type 2 diabetes were included, 49.2% were males. The mean duration of diabetes in males was 26.09 (20.95) months and that of females was 28.68 (20.54) months. The aetiological grouping revealed the following proportions: Type 1A-3.2%, Type lB-12.1%, LADA-5.7%, and “true” type 2 diabetes 79.0%. All the patients with Type lA were apparently, and rightly so, on “insulin-only” treatment even though they did not achieve optimal glycaemic control with HbA c % = 9.06. However the study patients who were type lB and LADA were distributed all over the treatment groups where most of them did not achieve optimal glycaemic control, range of HbA c of 8.46 -10.6%. The patients with “true” type 2 were also distributed all over the treatment groups where only subjects on ‘diet only’ treatment had good HbA c of 6.72% but those in other treatment groups did not achieve optimal glycaemic control of HbA c, 8.07 - 9.32%. Conclusion: Type 2 diabetes is a heterogeneous disease where clinical judgement alone does not adequately tell the various aetiological types apart without additional laboratory testing of C-peptide levels and GAD antibody status. This may partly explain the inappropriate treatment choices for the various aetiological types with consequent sub-optimal glycaemic control of those patients. INTRODUCTION
classification (2) sought to replace the previouscategories with a functional measure based on insulin
classification (1) subdivided diabetes according to
Type 2 diabetes is a heterogeneous disease
perceived need for insulin therapy. The WHO (1997)
with multiple causes revolving around beta cell
dysfunction and insulin resistance, the latter process
consecutively because they are relatively fewer in
is largely determined by obesity (3,4). However the
this clinic. Each recruited study participant was re-
cut-off level of obesity and the proportions thereof
evaluated for weight and height in the standard way
vary in populations. C-peptide is considered a good
to ascertain the BMI. A detailed history of diabetes
marker of insulin secretion because of its equimolar
including date of onset, family history, the
secretion with insulin, negligible hepatic extraction
contemporary and past treatment modality or profile
(5-7) and constant peripheral clearance at different
were obtained and recorded. Family history of
plasma concentrations and in the presence of
diabetes was recorded as present or absent; treatment
alterations in plasma glucose concentrations (7,8).
choices as; diet-only, oral glucose lowering agents-
Fasting C-peptide alone is easy to obtain and correlates
only, insulin only and combined insulin and oral
agents. There were multiple generics of the oral
agents (both sulphonylureas and metformin) in use
largely guided by the perceived class of insulin
by the study patients either as single or combination
requiring or non-insulin requiring types, this
oral agents therefore no further attempts were made
classification being informed by clinical judgement
to define them in details beyond their categories as
based on age of onset and obesity status. It is unclear
oral glucose lowering agents. The information was
whether the defects in insulin- sensitivity and insulin
captured as the number (proportion) of study patients
secretion occur in parallel and progress at the same
on each treatment modality/choice. Laboratory work-
velocity through the time course of the disease once
up of fasting C-peptide levels, GAD antibody status,
the diagnosis has been made (9-12) and particularly
glycated haemoglobin (HbAIc) and fasting glucose
when the diabetes is being treated by mono or
were done. A sample of 8mls of venous blood was
multiple drug strategies. Suffice to say that glycaemic
withdrawn from antecubital vein. C-peptide was
control of diabetes has remained largely an elusive
determined by Elisa (human bioassay technique, US
goal in many regions of the world even where
biological, a solid two-site enzyme immunoassay with
resources are considered to be relatively abundant.
a lowest detection limit of 0.3 ng/ml and precision
Hattersley (13), opines that treatment decisions in
CV<10%. GAD antibody status was also determined
diabetes should depend on genetic aetiology of
by Elisa technique (diaplets anti-GADplus, Roche
diabetes and not just on age of onset, Body Mass
Applied Science Division for Quantitative
Index (BMI) and severity of hyperglycaemia. He
Determination of Antibodies to GAD-65). Data on C-
admits that high costs remain a deterrent to detailed
peptide and GAD antibody status were used to re-
testing in diabetes care. This study first classified
categorise patients as type lA autoimmune, type IB-
patients with type 2 diabetes on clinical grounds,
idiopathic, latent autoimmune diabetes of adults
then re-categorised them using laboratory tests and
(LADA) and “true’ type 2 diabetes. Upon re-
evaluated the therapeutic choices they were using
categorisation the study participants were evaluated
that had been initiated based on clinical judgement.
for clinical characteristics, current therapeutic choicesin use and respective levels of glycaemic control
MATERIALS AND METHODS
achieved. The data were summarised in categorieswhere appropriate and continuous variables were
Subjects: Patients with clinically defined type 2
summarised in means and standard deviation and
diabetes were recruited and included in the study.
proportions. Differences in means between males
Type 2 diabetes was defined as diabetes mellitus of
and females and various treatment modalities were
onset at age 40 years and above or if less than 40 years
tested by students t-test where indicated. The level of
the person had been on oral glucose lowering agents
statistical significance was taken at p<0.05.
for at least six months. Furthermore, the patientswho were classified as obese by body mass index
(BMI); ( BMI > 25kg m2) were systematically sampledwhere every other patient fitting the inclusion criteria
A total of 124 subjects were included in the study.
was enrolled on each clinic day. This clinic conducts
Their clinical and laboratory characteristics are
only one major diabetes clinic each week. The non-
obese (BMI <25kg/m2) patients were recruited
Characteristics of the study subjects by gender
Treatment choicesproportion of patients Diet-only
Statistically significant differences between males and females
Characteristics of the study population by their aetiologic typesAetiologic types, therapy at enrolment and mean glycated haemoglobin of the study subjects
Virtually all patients categorised as type IA were on treatment with insulin only, howeverthey were not reaching glycaemic targets.
Other types (lB and LADA) of diabetes were on various therapies but did not achieveoptimal glycaemic control.
“True” Type 2 diabetes were also receiving multiple therapies without reaching desiredtargets except those on “diet - only” therapy. DISCUSSION
that BMI does not seem to influence treatmentresponse with either class of drugs (15-17) even though
At recruitment of subjects into this study, the defining
BMI is used to inform treatment choices. Whatever
characteristics were clinically defined type 2 diabetes
factors that are considered in making choices of
with a body mass index of either < 25 Kg/m2 or above
therapy adequate glycaemic control is the main goal
25 Kg/m2. Other clinical and laboratory parameters
of therapy in diabetes both in type 1 (18) and type 2
were subsequently determined which unmasked a
previously unknown heterogeneity within those
The significance of this study is that all study
patients who were clinically defined as type 2
participants were clinically defined to have type 2
diabetes and followed up as such. Hence their
therapeutic choices were essentially those designed
patients with type 2 diabetes and obesity (BMI >25
for such patients. It is therefore no wonder that the
Kg/m2) should be treated with metformin as first
subjects who were later found to fit the category of
line and the non-obese (BM1< 25Kg/m2) should be
type 1 B diabetes were on oral agents with or without
given either sulphonylurea alone and/or combination
insulin. The oral glucose lowering agents included
with metformin. The message implied is that BMI
metformin and sulphonylureas (either glibenclamide
or chlorpropamide) in various dosages.
Probably BMI of our study patients was used
On re-categorising the patients by laboratory
to inform the primary clinicians of the perceived
testing (C-peptide levels and GAD antibody status)
appropriate choices of treatment. Some studies have
the patients fell into the various types of diabetics
looked at what factors including BMI ( as a measure
shown including type lA (autoimmune) and IB
of obesity) may predict response to treatment with
(idiopathic), latent autoimmune diabetes of adults
sulphonylureas or metformin and they suggested
(LADA) and ‘true’ type 2 diabetes.
The glycaemic control remained sub-optimal
higher BMI than the other aetiologic types. We did
in all those patients who remained ‘true’ type 2,
recognise that poor glycaemic control may not wholly
LADA and even those who were coincidentally type
be attributable to beta cell and/or insulin resistance
1 and supposedly on rightful insulin- therapy at the
factors but the mind of the patients may also be
time of enrolment (Table 3). Indeed only ‘true’ type 2
involved .The patients’ attitudes and perceptions and
diabetic patients on diet-only therapy had good
their participation in self-care are particularly
glycaemic control. The better glycaemic control in
important in improving therapeutic goals of glycaemia
the diet-only treatment group has been observed
(22), although they were not evaluated in the subjects
before in this clinic although we did not do C-peptides
in that study (20). A significant contribution from
Type 2 diabetes is a progressive disease (11) in
their adequate endogenous beta cell function, read
spite of therapies that are in use at onset of the disease
high C-peptide levels, explains the superior control
(23). There are no immediate therapeutic answers to
declining beta cell function of type 2 diabetes. ADOPT
Achieving glycaemic targets in type 2 diabetes
study (24) was a step towards this direction where
remains a major challenge during their clinical care.
preservation of beta cell was an outcome measure.
Cook et al (21) demonstrated that delayed or
Similarly there is no consensus, so far, on definition
insufficient intensification of pharmacological
(25) and management (26) of LADA. Pozzilli et al (26)
management is a cause of failure to attain glycaemic
have suggested that therapy which would influence
goals in their urban African-American- population.
the speed of progression towards insulin dependency
Our study has revealed the limitation of clinical
and in the process protect residual C-peptide secretion
judgement for telling the type of diabetes with
preferable for latent auto-immune diabetes of adults
certainty so that therapy can be optimised. However
clinical judgement has not been condemned
Insulin availability and accessibility to those
wholesome by this study. Rather it seems to suggest
who need it, especially in sub-Sahara Africa, is still
the need for early insulin therapy in the lean (BMI<
precarious (27). Even where insulin is already
25 Kg/m2) type 2 diabetic patients in this population
available, there is inertia in initiating patients with
who are likely to be the more heterogeneous group
type 2 diabetics on it (28). Our study patients had
with higher proportion of aetiologic type 1 diabetes.
diabetes for five years and less apparently many of
Classification of diabetes is still evolving and so far
them, maybe, needed either basal insulin or just
inconclusive. Consequently, therapeutic approaches
optimisation of the appropriate choice of therapy at
to types of diabetes as currently classified (by clinical
judgement) provide a lot of room for debate and use
In conclusion, successful glycaemic control in
of various treatment choices, maybe inappropriately,
patients with diabetes mellitus will require more
although that is what is universally available to
understanding of the disease processes in the various
clinicians in routine clinical practice.
classes, the operating clinical-laboratory predictors
Our study did cross-sectional fasting C-peptide
for the disease class/type and the appropriate and
assay where the extent of sulphonylurea stimulation
optimal therapeutic choices. Therefore, correctly
effect in patients using them could not be under-
classifying diabetes at the earliest time of clinical care
estimated even though the glycaemic control was sub-
would facilitate effective advice to the patient and
optimal. Either the beta-cell stimulation was sub-
inform the preparation for an individualised
optimal with contemporary doses that were in use or
treatment programme. This approach will secure
the peripheral insulin resistance was the determining
maximum participation in self-care of each patient
factor that was not addressed in therapy. Alternatively,
with diabetes. When patients were more satisfied
both beta cell stimulation and peripheral insulin
with their physicians’ communication skills (29) and
resistance were inadequately addressed, especially
participate more in their own treatment (30), they
amongst patients re-categorised as “true” type 2
were found to be more adherent to self-care
diabetes whose duration of diabetes was five years or
recommendations and achieve better health
less when they were expected to retain some insulin
outcomes. Not all hyperglycaemia is the same, states
secretory capability. The contribution of peripheral
Fowler (31). The patients living with diabetes and
insulin resistance was implied by the relatively high
their healthcare providers need to know as much in
levels of C-peptide in a significant proportion of our
order to embrace the varied therapeutic options and
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