© SUPPLEMENT TO JAPI • april 2011 • VOL. 59 13
Insulin Therapy at Onset of Type 2 Diabetes Mellitus
– A New Concept
BK Sahay
Abstract
In this study, insulin therapy was initiated at onset of disease in patients whose fasting blood glucose was more than
250mg/dl. All enrolled subjects were treated with human premixed insulin (30/70) administered subcutaneously twice
daily before breakfast and before dinner. A total of 113 subjects entered the study fulfilling the inclusion criteria. Good
glycaemic control was achieved in a few days. The dosage requirement of insulin came down gradually after control was
achieved as manifest by hypoglycaemia – leading to withdrawal of insulin. Some of them were managed with diet and
exercise alone. Others required small doses of oral antidiabetic agents (OAD). There were no cases of secondary failure
to OADs. Ten cases are on average duration of follow-up of 10 years. Two cases are under good control with diet and
exercise alone, seven on treatment with oral hypoglycemic agents and one of them requiring insulin to maintain HbA1c
below 7%. Thus insulin therapy at onset provides an opportunity to correct all the underlying pathogenic mechanisms i.e.
glucotoxicity, lipotoxicity and prevents beta cell apoptosis and suppresses inflammation, leading to beta cell protection.
Such timely intervention provides long term benefits, laying the foundation for the concept of beta cell preservation
rather that only replacing beta cell function. Hence we propose that all patients with type 2 diabetes should be offered
insulin therapy at the onset of their diabetes for a period of 2-4 weeks.
T
he discovery of insulin in 1922 brought in a remarkable
change in the outlook for both type1 and type 2 diabetic
patients who started surviving for longer periods till they
developed vascular complications or infections. The initial
preparations of insulin were crude extracts and had several
impurities and the volume of injections administered was
large and frequent doses were required Allergic skin reactions
and lipodystrophy were common and hypoglycemia was a
frequent problem. These problems were gradually overcome
by improvements in the purification techniques.
The development of oral hypoglycemic agents around mid
1950s provided an option to the physicians as well as the patient
to use either oral medication or to continue insulin. Often oral
hypoglycemic agents were preferred. Several workers also
attributed the development of the macro vascular complications
to insulin usage, suggesting that insulin was atherogenic.
This was the topic of debate for several years till it was finally
disproved by large scale studies like the UKPDS.1
Due to these factors and also the problems associated with
injecting insulin, it was not the preferred choice of therapy.
Hence, the issue of when and how early to initiate insulin in
patients with type 2 diabetes has remained an area of great
debate even till now. Clinicians and the patients are reluctant
to initiate insulin therapy in patients with type 2 diabetes due
to several barriers which exist.
However recent developments and newer knowledge
has brought in a change in these concepts. The data from the
DCCT2 and the UKPDS trials 2 have brought out the importance
of tight metabolic control in arresting the progression of the
complications as well as preventing the complications. We have a
better understanding of the aetiopathogenesis of type 2 diabetes.
There are two main defects the development of insulin resistance
and impaired beta cell function.3 We know that both genetic and
environmental factors like life style changes have a major impact
on both these defects. We have also learnt that insulin resistance
starts initially and gradually increases over a period of time then
Former Professor. & Head, Department of Medicine, Osmania Medical
College, 6-3-852/A, Ameerpet, Hyderabad 500016, INDIA
it plateaus off 4 while the beta cells initially compensate for the
insulin resistance by increasing insulin secretion, later when the
beta cells get exhausted, the insulin secretion starts declining
progressively resulting in hyperglycaemia. At the time of
diagnosis of diabetes 50% of the function of beta cells is already
lost. We have also a better understanding of the natural history
of diabetes. This newer knowledge has provided us to plan our
treatment strategies in a rational manner. The UKPDS study has
also provided answers to some of the unanswered questions,
does insulin or sulphonylurea therapies have any specific
advantage or disadvantage. It was shown that blood glucose
control is the key to the reduction of the complications and all
means of achieving it have the same effect. Intensive insulin
therapy does not produce any adverse effect on microvascular
or macrovascular complications or the quality of life.
Recent follow up studies on intensively treated subjects
of DCCT and UKPDS have shown the benefits of initial tight
metabolic control are carried forward for another 10 years even
though the control of diabetes was not so intense. This has been
called as the ‘metabolic memory’ 5 or ‘legacy effect’.6 This is a
compelling reason to effectively control hyperglycemia from the
time of diagnosis of diabetes.
Research in animal models and in patients with diabetes has
shown that glucose toxicity due to the hyperglycemia contributes
to both insulin resistance and beta cell impairment7,8 in animal
models chronic hyperglycemia is shown to lower beta cell mass
through the induction of apoptosis. It has been shown that short
bursts of hyperglycaemia blunt the insulin stimulated glucose
uptake9,10 resulting in increased insulin resistance. It has also been
demonstrated that correction of this hyperglycemia with use of
insulin, improves the insulin sensitivity.11 Acute hyperglycemia
also has an inhibitory effect on the beta cell insulin secretion
(glucotoxicity). High levels of circulating free fatty acids, seen
with the hyperglycemia also cause suppression of beta cell
insulin secretion (lipotoxicity). Insulin therapy corrects both the
lipotoxicity and glucotoxicity. Even short term insulin therapy
appears to result in long term improvements in blood glucose
control especially when administered in early stages. 12-15 Insulin
therapy offers several benefits. It improves beta cell function
14
by correcting the glucotoxicity and lipotoxicity. It reverses the
insulin resistance and imparts beneficial effects on the lipids.
Insulin is anti inflammatory. Overall it also improves the quality
of life. Hence it addresses all the pathogenetic mechanisms
playing a role in the development of type 2 diabetes. Therefore
there is a rationale and role for insulin in the treatment of type
2 diabeties. It can control hyperglycemias in all cases when
administered in appropriate dose.
Based on these observations some workers have advocated
initiating insulin therapy early in the course of type 2 diabetes
in an attempt to preserve beta cell function and improve long
term glycaemic control.13
Material and Methods
We conducted a study in which insulin therapy was initiated
at onset of disease in patients whose fasting blood glucose was
more than 250mg/dl. The inclusion criteria were i) diagnosis
of diabetes established by the WHO criteria ii) detection of
diabetes < 1 month from the date of presentation. iii) severe
hyperglycemia at presentation with fasting plasma glucose >
250 mg/dl. The exclusion criteria were as follows i) presence
of diabetic ketoacidosis or hyperosmolar non-ketotic coma
at presentation or in the past 3 months, ii) presence of acute
myocardial infarction, stroke, trauma or active infections iii) not
willing to take insulin or comply with the follow up.
All patients meeting the above criteria were enrolled into
the study and they were given dietary advice which included
the caloric intake provided as per the ideal body weight and
activity, advice regarding exercise which emphasized the need
for regular physical activity for 30-45 min /day to be started after
at least one week of therapy with insulin. All enrolled subjects
were treated with human premixed insulin (30/70) administered
subcutaneously twice daily before breakfast and before dinner.
The insulin therapy was continued until optimal glycaemic
control was achieved or patients developed hypoglycemia and
subsequently they were either continued with diet, exercise
and OHA.
Results
Patients with type 2 diabetes registered in the clinic from
March 1994 – 2000 were 9980. Of these 113 cases fulfilled these
criteria, of these 38 cases (33.62%) did not come for 1st follow up
(non acceptors / drop out 5) Number of patients who came for
follow up was 75 (66.38%) of these long term follow up of more
than 1 year was in 24 (32%).
Good glycaemic control was achieved in a few days. The
dosage requirement of insulin came down gradually after
control was achieved as manifest by hypoglycaemia – leading
to withdrawal of insulin. Some of them were managed with
diet and exercise alone others required small doses of OHA.
There were no cases of secondary failure to OHA. 10 cases are
on average duration of follow up of 10 years. 2 cases are under
good control with diet and exercise alone, 7 on treatment with
oral hypoglycemic agents and one of them requiring insulin to
maintain HbA1C below 7%.
Discussion
Initiation of insulin therapy at onset results in good glycaemic
control with rapid correction of glucotoxicity. The beta cell
function is preserved and secondary failure to OHA is prevented
with correction of glucotoxicity. There is improvement in both
© SUPPLEMENT TO JAPI • april 2011 • VOL. 59
endogenous insulin secretion and insulin sensitivity. This is in
contradistinction to the observations in UKPDS where it was
found that there is a continuous decline in beta cell function
with on going need for additional therapy. Therefore such
therapy may be extremely cost effective because of anticipated
improvements in long term outcomes resulting in remission/
cure.
Ikova et al in 1997 demonstrated that induction of euglycaemia
using intensive insulin therapy at the time of clinical diagnosis
of diabetes could lead to a significant increase in the insulin
secretion and action and thus alter the clinical course of disease.16
They treated 13 newly diagnosed cases unresponsive to diet and
exercise with CSII for 2 weeks followed up with treatment with
diet alone. 9 patients retained good control with diet alone for
9 to 50 months (26 ± 4.8) while 4 cases were therapeutic failures.
They concluded that a significant proportion of type 2 diabetes
who fails to respond to dietary measures, short term IIT can
effectively establish responsiveness and achieve long term
glycaemic control without any medication. They demonstrated
a 6 fold increase in glucose disposal, an increase in C-peptide
secretion and improved insulin sensitivity.16
Sahay BK et al17 also reported that insulin therapy at onset
in patients with severe hyperglycemic without associated
infection, myocardial infarction and other stressful situations
led to good glycaemic control quickly and produced long term
glycaemic control with only life style measures or small does of
OHA. They concluded that in newly diagnosed type 2 diabetes
with elevated fasting glucose levels a 2 – 3 weeks course in
intensive insulin therapy can successfully lay a foundation for
prolonged good glycaemic control.
Alvarsson et al. in their study of 39 patients with type 2
DM diagnosed 0–2 years, who were randomized to either two
daily injections of premixed 30% soluble and 70% NPH insulin
or glibenclamide (3.5–10.5 mg daily).18 They were followed
up for 2 years. C-peptide– glucagon tests were performed
yearly in duplicate after 2–3 days of temporary withdrawal of
treatment. Early insulin versus glibenclamide treatment in type
2 diabetes temporarily prolongs endogenous insulin secretion
and promotes better metabolic control.
Scarlett et al demonstrated that two weeks of insulin therapy
reverses the insulin resistance and improves the insulin mediated
glucose disposal by six fold. Insulin provides benefits beyond
glycaemic control, improves beta cell function, reverses IR
has beneficial effects on lipids.19 They showed that short term
insulin therapy can induce long term glycaemic control in newly
diagnosed type 2 diabetics with severe hyperglycemic. Recently
similar studies were conducted by two groups in China.
In another study by Chen et al newly diagnosed type 2
diabetic patients with severe hyperglycemic were hospitalized
and treated with IIT for 10-14 days and randomized to received
either insulin or oral antidiabetics.20 They were reassessed at 6
months and one year. HbA1C and beta cell function were better in
the insulin treated group. A 6-month course of insulin therapy,
compared with OAD treatment, could more effectively achieve
adequate glycemic control and significant improvement of β–
cell function in new-onset type 2 diabetic patients with severe
hyperglycemia. Therefore evidence has emerged that short-term
intensive insulin therapy in newly diagnosed type 2 diabetes
could improve glycemic control associated with improved
insulin secretion
Weng et al studied the effect of intensive insulin therapy on
beta cell function and glycaemic control in patients with newly
© SUPPLEMENT TO JAPI • april 2011 • VOL. 59 diagnosed type 2 diabetes.21 382 patients were randomized to
CSII, MDI or OHA 2 weeks later followed up with diet and
exercise. More patients in the insulin groups achieved target
glycaemic control in shorter time 97.1% in 4 days 95.2% in 5 – 6
days Vs 83.5% in 9.3 days. The remission rates were higher in
the insulin treated groups 37.1% and 44.9% Vs 26.7% in OHA
(p=.0.012).21
Thus insulin therapy at onset provides an opportunity
to correct all the underlying pathogenic mechanisms i.e.
glucotoxicity, lipotoxicity and prevents beta cell apoptosis and
suppresses inflammation, leading to beta cell protection. Such
timely intervention provides long term benefits, laying the
foundation for the concept of beta cell preservation rather that
only replacing beta cell function. Hence, we propose that in
patients with type 2 diabetes should be offered insulin therapy
at the onset of their diabetes for a period of 2-4 weeks.
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