Insulin Secretion Capacity as a Crucial Feature to Distinguish Type 1 From Type 2 Diabetes and to Indicate the Need for Insulin Therapy – A Critical Discussion of the ADA/EASD Consensus Statement on the Management of Type 1 Diabetes in Adults

Abstract

In the recently published consensus statement on the treatment and management of type 1 diabetes issued by experts from the American (ADA) and European (EASD) diabetes societies, measurement of endogenous insulin secretion using fasting C-peptide is recommended as a diagnostic criterion. In contrast, our group recently suggested fasting C-peptide/glucose ratio (CGR) for the determination of endogenous insulin secretion. In addition, this ratio may turn out as a potential decision aid for pathophysiologically based differential therapy of diabetes. In this comment, the following points will be discussed: i) CGR as the basis of differential diagnosis of type 1 diabetes, ii) CGR as the basis of treatment decisions for or against insulin in diabetes, and iii) the ease of application of CGR in clinical practice. The use of CGR may complement the ADA/EASD recommendations and should provide a practical application in clinical practice.

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

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

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

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.

Conflict of Interest

The authors declare that they have no conflict of conflict of interest.

Acknowledgments

We acknowledge that Mr. Sven Bachofner (Sanofi) prepared [Fig. 3]. We also duly thank Prof Robert Wagner (University Hospital Düsseldorf) for the scientific discussions and critical reading of the manuscript.

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Publication History

Received: 13 June 2022
Received: 19 November 2022

Accepted: 23 December 2022

Article published online:
12 June 2023