An emerging new concept for the management of type 2 diabetes with a paradigm shift from the glucose-centric to beta cell-centric concept of diabetes - an Asian perspective

Figures & data

Figure 1. Paradigm shift from ‘glucose-centric’ to ‘beta cell-centric’ concept of T2DM. Under this concept, healthcare professionals and patients are able to consider beta cell preservation beyond glycemic control.

Table 1. Comparison among glucose-lowering agents with respect to glucose-lowering efficacy, risk of hypoglycemia, effect on weight, and beta cell protective effect.

	Glucose (HbA1c) lowering efficacy	Risk of hypoglycemia	Effect on weight	Beta cell protective effect
Metformin	Moderate to strong	Low	Neutral to loss	Yes
DPP-4 inhibitor	Moderate	Low	Neutral	Yes
GLP-1 receptor agonist	Strong	Low	Loss	Yes
SGLT2 inhibitor	Moderate	Low	Loss	Yes
α-glucosidase inhibitor	Modest	Low	Neutral	Yes
Thiazolidinedione	Moderate	Low	Gain	Yes
Insulin	Very strong	High	Gain	Yes
Sulfonylurea	Strong	High	Gain	No
Glinide	Modest to moderate	Low to moderate	Neutral	No

Figure 2. Plausible mechanisms of beta cell preservation by incretin drugs. Incretin drugs may preserve and/or improve functional beta cell mass through indirect and direct effects.

Table 2. Advantages and disadvantages of insulin and incretin-based drugs (DPP-4 inhibitors and GLP-1RAs).

	Insulin	Incretin-based drugs
Advantages	Most experience as anti-diabetic agent since discovery in 1921 Established safety Greatest glucose-lowering efficacy Similar efficacy even in patients with insulin deficiency Improves or preserves beta cell function, presumably through beta cell rest	Enhance glucose-dependent endogenous insulin secretion Suppress glucagon secretion in glucose-dependent manner Low risk of hypoglycemia Weight neutral for DPP-4 inhibitors and weight loss for GLP-1RAs Improve CV and renal outcomes for GLP-1RAs Improve and/or preserve beta cell function
Disadvantages	Hypoglycemia Weight gain Requires injection Induces hyperinsulinemia especially in peripheral tissues	Limited reduction in HbA1c (especially DPP-4 inhibitors) Limited efficacy in patients with insulin deficiency Gastrointestinal symptoms for GLP-1RAs Unknown longer-term safety

Figure 3. Paradigm shift in therapeutic strategy and pathophysiology of T2DM promoted by the development and launch of incretin drugs.

Table 3. Expected contributions of beta cell-centric concept in management of T2DM.

Integrates beta cell dysfunction and insulin resistance, the two components of the pathophysiology of T2DM which are often considered separately, into a single concept Clarifies the aim of treatment to reduce beta cell workload for both healthcare professionals and patients Enhances shared decision-making and person-centered diabetes care Establishes a consistent concept from prevention to treatment of T2DM, promoting early intensification of treatment and preventing clinical inertia Fosters seamless treatment of T1DM and T2DM in terms of beta cell preservation May help to understand differences in the pathophysiology of T2DM among ethnicities and/or regions Motivates not only patients with diabetes but also the general population to adhere to a healthy lifestyle, endorsing the advocacy of patients with diabetes

Figure 4. Hypothetical models of beta cell workload. For example, compared to subjects without obesity and diabetes (NONDM, reference), those with obesity and T2DM (ODM) are assumed to have greater insulin resistance (two-fold) but reduced beta cells (50%), resulting in a 4-fold increase in workload of individual beta cells, which could be attributable to progression of beta cell failure. This model indicates greater beta cell workload even in those with T2DM but without obesity (NODM), due to reduced beta cells, suggesting the importance of reducing beta cell workload in those with T2DM, irrespective of the presence or absence of obesity. This model also indicates greater beta cell workload in those with obesity but without diabetes (ONDM), due to limited beta cell expansion in response to obesity in humans, suggesting the importance of reducing beta cell workload in obese individuals without diabetes to prevent the development of T2DM.

Figure 5. Integration of concept of diabetes care into concept of ‘Mottainai’ for implementation of sustainable development goals (SDGs). Mottainai is a Japanese term containing the ‘4Rs’, reduce, reuse, recycle; 3Rs for ecology, and respect.

Figure 6. Updated management strategy for T2DM (modified from [8]). T2DM is characterized by progressive loss of functional beta cell mass (BCM) on a background of insulin resistance. Therefore, treatment of T2DM should focus on aiming at reducing beta cell workload to maintain optimal glycemic control. Lifestyle modification and weight loss remain the most fundamental and important therapy to improve insulin resistance. Pharmacotherapy should also be initiated to reduce beta cell workload, and thereby, metformin, SGLT2 inhibitors, and α-glucosidase inhibitors are preferred if tolerated. GLP-1RAs and SGLT2 inhibitors are expected to improve CV outcomes, and their use should be considered in those at high risk of CVD and those with heart failure and/or chronic kidney disease. DPP-4 inhibitors are expected to improve beta cell function, and better glycemic durability with initial combination therapy of a DPP-4 inhibitor with metformin compared with metformin monotherapy has been reported. Selection of the treatment option should be individualized according to a patient-centered approach. * Cardiorenal benefits have been shown in CVOTs.

Saisho Y. Beta cell dysfunction: its critical role in prevention and management of type 2 diabetes. World J Diabetes. 2015;6(1):109–124.

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