Key words insulin secretion - classification - subphenotype - C-peptide - treatment
Introduction
Significant innovations have recently been made in the treatment of type 2 diabetes.
There is now evidence that new antidiabetic drugs not only lower blood glucose but
also reduce mortality [1 ]. This has led to
guideline updates by the European Association for the Study of
Diabetes/American Diabetes Association [2 ]
[3 ] and also the European Society of
Cardiology [4 ]. The main change in these
guidelines is that the decision on treatment strategy is no longer solely based on
blood glucose deterioration (i. e. increase in HbA1c), but additionally
guided by the cardiovascular risk of the patient. However, these updated guidelines
do not address the probable pathologic underpinnings of the diabetes phenotype in
the specific patient. Importantly, 20–25% of patients with newly
diagnosed diabetes belong to the severe autoimmune diabetes and severe insulin
deficient diabetes clusters [5 ]
[6 ], implicating absolute insulin
deficiency. Failure to recognize insulin deficiency at an early time-point leads to
delayed glucose control, higher glycemic burden and eventually an increased
incidence of glycaemia-related complications such as retinopathy [5 ]. Therefore, detection of severe insulin
deficiency is critically important in an optimal diabetes treatment. We propose an
easy and feasible approach which allows a more precise diabetes therapy based on the
prevailing pathophysiological disorder.
Classification of Diabetes: New Subphenotypes of Diabetes
Classification of Diabetes: New Subphenotypes of Diabetes
The entity of type 2 diabetes is an aggregation of various disorders that are mainly
characterized by “elevated blood sugar”. In order to be able to
carry out a better and more specific therapy of diabetes, a precise
subclassification of diabetes is essential.
In 2018 a new classification of diabetes was introduced by the research group of Leif
Groop [5 ]. Five subphenotypes were derived
from cluster-analysis based on the variables BMI, HbA1c, age at diagnosis, presence
of GAD antibodies, insulin sensitivity, and insulin secretion.
The identified subtypes of diabetes are described as severe autoimmune diabetes
(SAID) which essentially reflects the hitherto known type 1 diabetes. The other 4
subphenotypes are labelled as severe insulin-deficient diabetes (SIDD), severe
insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-
related diabetes (MARD). It is important to note that these groups show
characteristic responses to therapy: for example, time for sustained treatment with
insulin was shortest in SAID and SIDD patients reflecting their impaired insulin
secretion. Furthermore, some of the new subtypes of type 2 diabetes are strongly
associated with secondary complications of diabetes (e. g. SIRD with
nephropathy [5 ], SIDD with polyneuropathy
[7 ]). This new classification will
hopefully allow a pathophysiologically based, more precise diabetes therapy in the
future. However, randomized controlled studies are needed that test different
therapies for different subtypes. Additionally, it is important to work with clear
and easy criteria that identify subphenotypes with high accuracy. For this purpose,
determination of endogenous insulin secretion plays an essential role.
Importance of Insulin Secretion
Importance of Insulin Secretion
Insulin secretion, based on fasting C-peptide determination and calculated with the
“homoeostasis model assessment 2” estimates of β-cell
function (HOMA2-B), is an integral part of the classification of the new
subphenotypes of diabetes. For example, the clinically most challenging
subphenotypes SIDD and SIRD [5 ] are mainly
characterized by low (mean±SD 48±29, SIDD) or increased
(150±47, SIRD) HOMA2-B, respectively. Furthermore, the subphenotype SAID
(type 1 diabetes) also features low insulin secretion (57±45). Therefore,
the assessment of insulin secretion is an important diagnostic tool for the
differentiation between insulin deficient diabetes and hyperinsulinaemic
diabetes.
Importantly, a considerably high number of new manifestations of autoimmune diabetes
is seen in older people. A study using a polygenic risk score based definition of
type 1 diabetes revealed that 42% of all new type 1 manifestations occur
after the age of 30 [8 ]. In contrast, only
38% of individuals with newly diagnosed type 1 diabetes receive insulin
therapy immediately [9 ]. This underlines
that a detection of insulin deficiency present in late onset autoimmune diabetes is
particularly important, since the failure of a timely initiation of insulin therapy
and/or an inadequate therapy with ketoacidosis-promoting agents such as
SGLT2 inhibitors could have fatal consequences for type 1 diabetes patients [10 ].
The C-peptide/Glucose Ratio (CGR)
The C-peptide/Glucose Ratio (CGR)
Measurement of C-peptide from blood serum or plasma is a reliable and well
standardized laboratory method to assess endogenous insulin secretion [11 ]. In contrast, measurement of insulin is
still not standardized and thus not well comparable between different laboratories
[11 ]. However, the complex calculation
of C-peptide-based endogenous insulin secretion using HOMA2-B which has been applied
in the study of Ahlqvist et al is not commonly performed by general practitioners
and diabetologists, mainly because this calculation is impractical and time
demanding. The determination of fasting C-peptide or C-peptide glucose ratio have
been shown to correctly classify insulin deficient type1 diabetes vs. type 2
diabetes [12 ]. Therefore, a simple
determination of C-peptide that is adjusted for the current plasma glucose
concentration could be similarly sufficient and more convenient than HOMA2-B to
identify insulin deficient patients needing insulin therapy.
We examined 3751 individuals from the Tuebingen Family study and Tuebingen Lifestyle
Programme with screen detected diabetes, prediabetes and normal glucose tolerance
(age 18–91 years, median 46 years) [13 ]
[14 ]
[15 ]. We performed 7349 five-points oral
glucose tolerance tests with measurement of glucose and C-peptide. The fasting
C-peptide / glucose ratio correlates well with HOMA2-B
(r²=0.74, p<0.0001) in the whole population ([Fig. 1a ]). In screen detected, newly
diagnosed patients with type 2 diabetes, an even stronger correlation is present
(r²=0.80, p<0.0001, [Fig. 1b ]). This correlation is higher than a simple fasting
–C-peptide without adjustment for plasma glucose (r²=0.47).
Note that not a single individual had a CGR below 2, and the median of CGR was 5.3
in the population with normal glucose tolerance, 6.4 in the prediabetic population
and 7.4 in the screen detected, newly diagnosed type 2 diabetic population (who did
not take any glucose-lowering therapy or dietary measures).
Fig. 1 a Association between fasting C-peptide / glucose ratio (CGR)
and HOMA 2-B in individuals with normal glucose tolerance, prediabetes and
newly diagnosed type 2 diabetes. b Association between fasting
C-peptide / glucose ratio (CGR) and Homa2-B in newly diagnosed type 2
diabetes. Vertical lines indicate proposed limits for insulin deficiency
(CGR<2) and non-insulin based therapy (CGR>5) c CGR
on day of admission in 330 individuals with diabetes admitted to hospital
for diabetes treatment, red lines indicate median CGR of the respective type
of diabetes
Fig. 2 Use of CGR for diabetes therapy.
DPP4i=Dipeptidylpeptidase-4 inhibitor; SGLT2i=Sodium
dependent glucose co-transporter-2 inhibitor; GLP1-RA=glucagon like
peptide 1 receptor agonist, TZD=thiazolidinedione,
SU=sulfonylurea.
We furthermore assessed fasting CGR in a population of 330 patients with known
diabetes (type 1 diabetes: n=71, type 2 diabetes: n=238 type 3
diabetes: n=21) admitted to our university hospital for diabetes therapy
(Fig. 1c). These patients were between 18–89 years old (median 58 years),
had a median HbA1c of 8.7% on admission (range: 5.8 and 16.4%), and
the median diabetes duration was 10 years (between 0 and 57 years of duration). In
this patient population, patients with a history of type 1 diabetes had a median
fasting CGR of 0.4 which was reduced to 0.1 when patients with short duration of
diabetes (≤2 years) were excluded. Patients with type 2 diabetes had a
median fasting CGR of 3.6 and with pancreatogenic (type 3c) diabetes a median
fasting CGR of 1.4 ([Fig. 1c ]).
As C-peptide is cleared by the kidney, fasting CGR could be inaccurate in renal
insufficeincy. Therefore, CGR should not be used in patients with a glomerular
filtration rate below 50 mL/min/1.73 m². Furthermore, CGR
should not be calculated in a state of severe metabolic decompensation, such as a
fasting plasma glucose above ~250 mg/dl, as glucotoxicity may
acutely but reversibly impair insulin secretion. Finally, there might be minor
differences between different C-peptide essays [11 ] which may affect generalization of limits for treatment
decisions.
Three Practical Steps for a Pathophysiologically Justified, More Precise Diabetes
Therapy (see [Fig. 2 ])
Three Practical Steps for a Pathophysiologically Justified, More Precise Diabetes
Therapy (see [Fig. 2 ])
Currently, guidelines for the treatment of diabetes mellitus do not adequately
address the various new subphenotypes of diabetes. Below we propose a simple concept
for a more precise subphenotype oriented diabetes therapy. The importance of
lifestyle intervention as a base for diabetes therapy is taken for granted.
Question 1: Is insulin needed?
This decision must be made at the beginning of a pharmacological diabetes therapy
or, even more important, when modifying therapy in a patient with inadequate
glycaemic control. There are two forms of insulin deficiency, autoimmune
diabetes (type 1 diabetes, SIAD) and severe insulin deficient diabetes (type 2
diabetes, SIDD). Both need to be treated with insulin based on a simple rule
that a specific hormone deficiency must be treated with the replacement of this
specific hormone to restore normal physiology. Here, this concept is desperately
needed because failure to treat insulin deficiency in diabetes can lead to
ketoacidosis, coma and death.
The initial question of whether a patient with diabetes requires insulin can
easily be answered by calculating the fasting CGR. A patient with HbA1c above
target and a CGR of less than 2 exhibits insulin deficiency and should therefore
be treated with insulin. No individual with normal glucose tolerance,
prediabetes or screen detected, newly diagnosed type 2 diabetes exhibits a CGR
below 2, as shown in ([Fig. 1a,b ]).
Patients with type 1 diabetes (among them newly diagnosed patients in remission)
show a median CGR below 1 ([Fig.
1c ]). Furthermore, a CGR below 2 equates to a HOMA2-B of 50 which is well
in the range of SAID and SIDD in the classification of Ahlqvist et al [5 ]. The lower the CGR, the more likely
a basal bolus insulin therapy is required. Furthermore, it has to be added that
an auto-antibody determination is clinically not helpful in answering the
question of whether or not to treat with insulin [8 ]
[16 ].
Another purpose of calculating CGR is the identification of patients who will not
necessarily require insulin treatment, because they exhibit a high insulin
secretion or insulin hypersecretion. However, it is challenging to locate a
threshold for this. One suitable approach may be to define a fasting CGR 5 as a
threshold. An argument for such a limit is that the median fasting CGR in a
large middle-aged population of healthy individuals is 5.3. Therefore, a fasting
CGR of >5 presumably indicates that there is enough endogenous insulin
secreted. Another argument for such a threshold comes from the study from
Sweden, where the non-insulin-treated diabetes group SIRD, that is characterized
by insulin hypersecretion and insulin resistance, had a mean HOMA2-B index of
~150 [5 ]. This corresponds to
a fasting CGR of 10 (Fig 1a/b).
Question 2: Is there a cardiovascular risk?
If it has been decided that an insulin therapy is absolutely necessary (CGR
<2), possible (fasting CGR 2–5) or to be avoided (fasting
CGR> 5), then it should be further decided whether a cardiovascular risk
exists to guide the appropriate oral antihyperglycaemic therapy. If such a risk
is present, SGLT2 inhibitors or GLP-1 agonists should be primarily used, as
studies show that they cause a reduction in cardiovascular mortality and
morbidity [1 ]. This is undisputed
unequivocally supported in both the current ADA/EASD and the ESC
guidelines [2 ]
[3 ]. Such a therapy is recommended
regardless of the level of HbA1c. However, it is also important in this
therapeutic decision to pay attention to the CGR, which indicates whether an
insulin deficient diabetes is present (CGR <2). Currently GLP-1 agonists
are not approved in type 1 diabetes, and only some SGLT2 inhibitors are approved
for this indication in Europe. If the CGR is less than 1 (= absolute
insulin deficiency, risk of ketoacidosis), SGLT2 therapy should be initiated
very carefully and never without insulin therapy.
Question 3: Old age and low HbA1c?
Milder forms of type 2 diabetes (MARD and MOD) are also described in the new
classification [5 ]. These are
characterized by slightly elevated HbA1c, higher age at onset and lower
incidence of complications. A de-escalation of pharmacological glucose-lowering
therapy could be considered for already initiated therapies, when there is a
sufficient endogenous insulin secretion (e. g. a CGR of more than 2) to
prevent decompensation of glucose metabolism. The possibility of de-escalation
should also depend from the cardiovascular risk and the HbA1c level. An HbA1c of
anything above 8% should only be accepted in exceptional cases. However,
HbA1c goals for different types of diabetes patients are highly individual, and
there is no broad consensus regarding the limits [17 ].
Again, fasting CGR also plays an important role in therapeutic decisions in
favour or against insulin therapy. If insulin deficiency exists (CGR
<2), discontinuation of insulin is not recommended in any patient
including elderly patients, irrespective of age and HbA1c. When the CGR is lower
than 1, the discontinuation of insulin is potentially life-threatening. Such
values are not only common in type 1 diabetes but can also occur in older type 2
diabetes patients with a disease duration of decades. If the CGR is below 1,
SGLT2 and/or GLP-1 therapy which could be indicated by cardiovascular
risk should be used carefully and never without insulin therapy.
Summary
The application of fasting CGR in patients with diabetes provides a practical way
for selecting a more precise diabetes therapy according to the concept of the
newly proposed diabetes subphenotypes. Three simple steps can help choosing a
pathophysiologically justified therapy. However, prospective randomized clinical
studies in precision diabetes therapy are still missing, and regulatory
considerations have to be taken into account [18 ]. Insulin deficiency is an essential
factor determining antidiabetic therapy. Therefore, endogenous insulin secretion
should always be assessed when starting a new therapy or changing the treatment
regimen.
Author Contributions Statement
Author Contributions Statement
A.F. analysed the data and wrote the manuscript. A.F., M.H., A.P., H-U.H and R.W.
contributed to data acquisition. All authors contributed to the interpretation of
data and edited the manuscript. All authors have reviewed the manuscript.
