Key words insulin secretion - c-peptide - treatment - classification
Endogenous insulin secretion is the critical pathophysiological component in diabetes
mellitus [1 ]. It is a determinant both for
the conventional classification into type 1 and type 2 diabetes mellitus [1 ]
[2 ] and in the more recent classification according to cluster-related
subtypes [3 ]
[4 ]. It can be measured simply as the
C-peptide/glucose ratio (CGR) [5 ].
It is suggested that the ADA/EASD consensus statement on the treatment and
management of type 1 should be amended to include the CGR determination. In this
regard, three points are discussed below.
C-Peptide Glucose Ratio as a Basis for Differential Diagnosis of Type 1
Diabetes
C-Peptide Glucose Ratio as a Basis for Differential Diagnosis of Type 1
Diabetes
In the ADA/EASD Consensus Statement, a flowchart for the investigation of
suspected type 1 diabetes in newly diagnosed adults is provided ([Fig. 1 ]). The critique of this scheme is
summarized in the flowchart shown in [Fig.
2 ]. The primary aim of the differential diagnosis of diabetes is to
differentiate type 1 diabetes from type 2 diabetes. It is important to diagnose the
fundamental and therapy-decisive pathophysiology of type 1 diabetes, namely the
absolute and life-threatening insulin deficiency. Thus, the items listed in [Fig. 1 ], such as age at manifestation and
monogenetic forms of diabetes with associated genetic analyses, recede into the
background. In particular, the age limit of 35 years, which induces a different type
1 diabetes incidence and different diagnostic approach in the flowchart of the
ADA/EASD group, is unfounded because, according to a recent study,
42% of all new type 1 diabetes manifestations occur after 30 years of age
[6 ].
Fig. 1 ADA/EASD Consortium flow chart for screening for suspected type 1 diabetes in newly
diagnosed adults, based on data from white European
populations. Figure with permission from Holt et al. (Holt RIG, DeVries JH, Hess-Fischl
A et al. The management of type 1 diabetes in adults. A
consensus report by the American Diabetes Association [ADA] and the European Association
for the Study of Diabetes [EASD]. Diabetologia 2021;
64: 2609–2652) [rerif]
Fig. 2 A simplified alternative proposal for testing suspected type 1
diabetes in newly diagnosed adults
The key point in the differential diagnosis is the measurement of endogenous insulin
secretion since type 1 diabetes is defined as severe insulin deficient (with or
without autoimmunity). However, this deficit is inadequately defined with C-peptide
measurement alone, as suggested by the ADA/EASD Consensus Statement. The C-peptide
level is strongly correlated with glucose level since glucose is the physiological
trigger for insulin secretion. Thus, the C-peptide value must be adjusted to the
currently prevailing glucose value, preferably by dividing the C-peptide value (in
pmol/L) by the simultaneously measured glucose value (in mg/dL, CGR) [5 ]
[7 ]. The measurement is best carried out in the fasting state, as there is
less fluctuation in the values and postprandial triggers of insulin secretion, such
as incretins, play a lesser role.
As already pointed out in the recently published commentary on the CGR [5 ], an insulin deficiency, and thus, a need
for insulin therapy must be assumed if the CGR is less than 2.
To demonstrate the superiority of the CGR compared to a pure measurement of
C-peptide, one only needs to assume a C-peptide value of 300 pmol/L, which
excludes type 1 diabetes according to the ADA/EASD Consensus. If the blood
glucose value measured at the same time is 90 mg/dL, sufficient
insulin secretion can be assumed. However, if the blood glucose is 200 or even
250 mg/dL (CGR 1.5/1.2) at the same C-peptide level of 300
pmol/L, a severe insulin deficiency is present, and type 1 diabetes must be
suspected.
It is important to note that many people with a new onset type 1 diabetes still may
have a residual β-cell function at the time of diagnosis and during the
remission phase. Therefore, in these situations, CGR will misclassify people with
type 1 diabetes and residual β-cell function. Here, repeated measurements of
CGR and an additional measurement of antibodies might be useful, as shown in [Fig. 2 ]. However, it has to be emphasized
that the main purpose of measuring the CGR is to predict the need for insulin
therapy (see paragraph 2).
C-Peptide Glucose Ratio as a Basis for Insulin Therapy Decision in
Diabetes
C-Peptide Glucose Ratio as a Basis for Insulin Therapy Decision in
Diabetes
Differential diagnosis of diabetes mellitus is important, but even more important
is
the subsequent treatment decision [7 ]. If
there is an absolute lack of endogenous insulin secretion, treatment with insulin
is
necessary, whether autoantibodies are present or not. In the case of people with
type 1 diabetes manifestation at an older age, a very long remission phase with
relatively high endogenous insulin secretion (high CGR) may be present. Depending
also on the HbA1c value, insulin therapy can be postponed. Alternatively, low-dose
insulin therapy can be started with once-daily basal insulin. In [Fig. 2 ], the blackening of the
“therapy bar” indicates that the lower the CGR, the more likely
insulin therapy is considered or mandatory. The limits of a CGR of less than 2,
which argues for insulin therapy, and greater than 5, which argues against insulin
therapy, should not be viewed in absolute terms but rather as guidance to aid
treatment decisions.
The classification into subtypes of diabetes, which should enable precision
diabetology, has so far been very limited by the different methods and the complex
investigations required and a large number of parameters for classification and
phenotyping [8 ]
[9 ]. As recently pointed out by our group
[5 ], CGR provides a therapeutic
decision aid that is useful in everyday clinical practice and can actually lead to
more precise diabetology. However, there is a substantial overlap in CGR between the
types of diabetes [5 ], indicating that
this is not an accurate way of differentiating across these endotypes of
diabetes.
C-Peptide Glucose Ratio in Clinical Practice
C-Peptide Glucose Ratio in Clinical Practice
Beside the homeostasis model assessment of the b-cell function (HOMA-b) index, there
are other published indices using fasting C-peptide and fasting glucose in different
complicated formulas with different multipliers. Among them are the secretory units
of islets in the transplantation index (SUIT) and the fasting serum C-peptide
immunoreactivity index (CPI) [7 ]. This
makes such indices rather unusable in everyday clinical practice. In contrast,
fasting CGR is easy to determine by mental calculation. However, different units of
measurement are reported by different laboratory providers (C-peptide in
pmol/L or µg/L), blood glucose in mmol/L or
mg/dL). [Fig. 3 ] shows the simple
determination of the CGR for different units by means of a nomogram. From this, a
differential therapy may be derived, which is explained in more detail in our
previous commentary [5 ]. Briefly, at a
CGR<2 (C-peptide in pmol, glucose in mg/dL), pink box Fig3), insulin
therapy is needed, and the lower the CGR, the more so with a basal and bolus insulin
regimen. With a CGR between 2 and 5 ([Fig.
3 ] blue box), basal insulin therapy in combination with other antidiabetic
agents is necessary. The type of non-insulin antidiabetic agents depends on
cardiovascular risk factors and concomitant diseases. With a CGR above 5 ([Fig. 3 ] green field), insulin therapy is
usually not necessary; sufficient endogenous insulin secretion exists. Non-insulin
antidiabetic agents are then used, again depending on the presence of cardiovascular
risk factors [5 ]. However, the focus of
the differential diagnostic and differential therapeutic approach always is to use
CGR to quickly identify those patients who need immediate insulin therapy. This can
be easily done by the offered diagram. The question of endogenous insulin deficiency
and the need for insulin therapy also arises repeatedly during the course of chronic
progressive type 2 diabetes and can also be easily assessed with CGR determinations
during the course of the disease.
Finally it is important to emphasize that the CGR must not be used in chronic kidney
disease (GFR below ~50-60 ml/min/1.73m²). C-peptide
is cleared by the kidneys and therefore the CGR is measuered falsely elevated in
renal insufficiency. Furthermore, different C-peptide assays give different results
[10]. This illustrates the relatively arbitrary nature of the specified CGR levels
for therapy decisions.
Fig 3 Nomogram for simple determination of fasting C-peptide-glucose
ratio (CGR; C-peptide in pmol/L, glucose in mg/dL) as a measure for
estimation of endogenous insulin secretory capacity. Different units of
measurement are reported by different laboratory providers (C-peptide in
pmol/L or µg/L), glucose in mmol/L or mg/dL). The normogram can be
used for easy and simple determination of the CGR for different units.
C-peptide was measured with Siemens ADVIA Centaur XPT.; Pink field:
CGR<2, insulin secretion deficit. Insulin therapy needed; the lower
CGR, the more likely basal-bolus insulin therapy.; Blue field:
CGR2–5, impaired endogenous insulin secretion. Basal insulin therapy
in combination with other antidiabetic agents.; Green field: CGR>5,
preserved endogenous insulin secretion. Usually, no insulin therapy needed,
but oral antidiabetic agents and incretin analogs.; Figure courtesy of Mr.
Sven Bachofner (Sanofi).
Summary
According to international consensus, insulin secretory capacity is an important
factor in the differential diagnosis and differential therapy of diabetes mellitus
[1 ]. Simple ratios (CGR) and
nomograms, as presented here, help to determine insulin secretory capacity in
clinical practice. The potential benefit of the additional cost and administrative
work in calculating the CGR needs to be determined in prospective studies before it
may be introduced into guidelines.
