Noval classification of diabetes mellitus

Noval classification of diabetes mellitus Professor Mohammed Ahmed Bamashmos Professor of internal medicine and endocrinology Faculty of medicine Sanaa University

Ahlqvist et al. performed a data-driven cluster analysis using six variables (glutamate decarboxylase antibody [GADA] level, age at diagnosis, body mass index (BMI), haemoglobin A1c [A1c], and homeostasis model assessment estimates of beta-cell function (HOMA2-B) and insulin resistance (HOMA2-IR)) at the onset of diabetes mellitus in a Sweden and Finland cohort. They identified five exclusive subgroups [13]. Remarkable differences were reported in the cumulative incidence of diabetic complications among the five subgroups. The reproducibility of this classification of adult-onset diabetes mellitus has been validated by reports on American and Chinese [14], German [15], Denmark [16] and Japanese [17] populations

The sub-classification based on the cluster analysis of Ahlqvist et al. [13] may have an advantage over the others because it uses simple but pathophysiologically feasible factors and is proven to be applicable over ethnic and racial differences to estimate diabetic complications [14], [15], [16], [17]. The sub-classification may provide a new framework for personalised diabetes treatment of established and/or novel complications [18]. However, the rationale and strategy of antidiabetic treatment for clustering-based sub-classification have not yet been fully discussed [19]. This review aimed to inform readers about the current knowledge and perspectives on potential therapeutic strategies based on clustering-based sub-classifications of adult-onset diabetes mellitus.

Current classification of adult-onset diabetes mellitus: T1DM and T2DM There is an international consensus on the sub-classification of T1DM into three subtypes [1], [2]: acute-onset [20], slowly progressive [20], [21], and fulminant [22] depending on the mode of onset and progression. In contrast to T1DM, there is no international consensus on the sub-classification of T2DM. Obese and non-obese subclasses of T2DM are often used in current clinical practice. However, the pathophysiological differences between obese and non-obese T2DM patients remain to be elucidated. We discussed several issues on current classification of T1DM and T2DM.

T1DM T1DM occurs due to autoimmune β-cell destruction, usually leading to absolute insulin deficiency. Environmental factors such as viral infections and genetic factors such as the human leukocyte antigen (HLA) allele are linked to β-cell destruction. Autoantibodies against islet antigens are often detected in the early stages of the disease [1], [2], [3]. Representative courses of the three types of T1DM are illustrated based on disease onset and progression [1], [20], [21], [22] (Fig. 1A).

Acute-onset T1DM presents as hyperglycaemic symptoms and an abolished insulin secretory capacity, typically over several weeks to several months (Fig. 1A) [23]. Latent autoimmune diabetes in adults (LADA) or slowly progressive type 1 insulin-dependent diabetes mellitus (SPIDDM) is characterised by late age at onset and progressive β-cell failure, both of which are associated with an initial non-insulin-requiring state but an ultimate insulin-dependent state after several years [3], [22]. In fulminant T1DM, β-cell destruction, hyperglycaemia, and ketoacidosis progress extremely rapidly, showing no detectable insulin levels within one week [22]. Numerous acute-onset and all LADA/SPIDDM, but not fulminant, cases feature islet autoantibodies [1], [20], [21], [22].

. 1. Representative changes in plasma glucose and insulin levels during onset in type 1 diabetes mellitus (T1DM) and obese and lean type 2 diabetes mellitus (T2DM): a hypothetical model. A. T1DM. T1DM is classified as acute, slowly progressive and fulminant based on the manner of onset and progression [2], [20], [21], [22]. Acute T1DM (AT1DM) typically develops hyperglycaemic symptoms along with an abolishment of the insulin secretory capacity over several weeks to several months [23]. Latent autoimmune diabetes in adults (LADA) or slowly progressive type 1 insulin-dependent diabetes mellitus (SPIDDM) is characterized by late age at onset, progressive β-cell failure which is associated with an initial non-insulin-requiring state and an ultimate insulin-dependent state over several years, and persistent islet cell autoantibodies [21]

Fulminant T1DM, in which the process of β-cell destruction and the progressions of hyperglycaemia and ketoacidosis are extremely rapid shows no detectable insulin levels and severe hyperglycaemia within the first week [22]. B. T2DM. Although fasting and postprandial glucose levels are altered to similar levels before and after the onset of diabetes in lean and obese T2DM (upper panel), insulin sensitivity (dotted line) and postprandial insulin levels (solid line) are quite different for the two phenotypes of T2DM. In obese T2DM (red lines), insulin resistance increases decade(s) before the onset of diabetes and fasting (not shown), and postprandial insulin levels rise to compensate for insulin sensitivity, causing hyperinsulinemia

β-cell failure or β-cell loss lessens hyperinsulinemia and leads to the development of diabetes mellitus, which gradually and progressively causes impaired insulin demand (a relative deficit of insulin) throughout the process of diabetes mellitus spanning decades. Obese T2DM can be classified into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) [35]. In lean T2DM (blue lines), insulin sensitivity is not severely altered, but β-cell function is genetically low [5], [30]. As β-cell dysfunction progresses with aging and daily glycaemic overload by consuming inappropriate foods, the intrinsic insulin secretory capacity declines over decades, finally leading to the onset of T2DM. Of note, the classification of T2DM into two types is convenient application for clinical use and there are large differences in the degree of insulin resistance and diabetic complications within obesity (MHO vs. MUO) and lean diabetes. *Lipodystrophy, a rare type of lean T2DM, denotes a lean but insulin-resistant phenotype [24], [36],

T2DM Obesity is a major risk factor for T2DM onset since it increases insulin resistance through the accumulation of ectopic fat, such as in the liver and the skeletal muscle [24], [25], [26], [27]. In Europe and the United States, T2DM onset and progression have mainly been described as a model of obesity-related processes [28]. However, a certain proportion of lean, non-obese individuals also develop T2DM [29], [30]. As clarified in studies using cluster-derived classification, the proportion of individuals with severe insulin-deficient and non-obese diabetes in Europe [13], the United States [14], and Japan [17] was ∼ 18%. Therefore, T2DM onset and development in Asians and non-Asians populations may be similarly divided into two major subtypes: obese insulin-resistant and lean insulin-sensitive. We thus illustrated the natural courses of hyperglycaemia, insulin sensitivity, and postprandial insulin levels in T2DM as two typical models (lean vs obese) (Fig. 1B

In obese T2DM (Fig. 1B), obesity, primarily due to overeating and decreased physical activity, lowers insulin sensitivity in proportion to visceral and ectopic fat excesses in the liver and the skeletal muscles, increasing the insulin secretory capacity by compensatory β-cell hypertrophy [31], [32]. However, when this hyperinsulinemic compensation begins to fail, postprandial and fasting plasma glucose levels rise, leading to the onset of T2DM. The insulin secretory capacity declines over decades, whereas the low insulin sensitivity remains unchanged. Previous longitudinal studies support this notion in obesity-related consequences for trajectories of glycaemia, insulin sensitivity, and insulin secretion before the diagnosis of T2DM in Pima Indians [33] and the Whitehall II study [34].

In contrast, there are few models of lean T2DM for the trajectories [5], [30]. In lean T2DM (Fig. 1B), it is assumed that insulin sensitivity is generally not severely altered but β-cell function is genetically low [5], [30]: as β-cell dysfunction progresses with age and daily glycaemic overload by the consumption of inappropriate foods, the intrinsic insulin secretory capacity declines over several decades, finally leading to the onset of T2DM. This group is characterised by relative hypoinsulinemia at the onset of T2DM, and a certain proportion of patients will require insulin treatment during the long course of diabetes.

Prediabetes has heterogeneous pathogenesis and ability to predict progression to full-blown T2DM [35]. The critical phenotype of prediabetes, non-obese or obese, enables the stratification of cardiometabolic risk [35]. In the obesity phenotype, prediabetes may coexist with either metabolically healthy obesity (MHO) or metabolically unhealthy obesity (MUO) [36]. Compared to MUO, MHO has a higher capacity for storage in the subcutaneous fat. It may explain less visceral obesity, less ectopic fat and subsequent lower insulin resistance in MHO [36]. Such phenotypes of body fat distribution can be linked to differences in the risk of atherosclerotic cardiovascular disease (ASCVD), dementia, and cancer between prediabetes and diabetes with MUO and those with MHO [37

There are racial differences in the frequency of the obese and non-obese groups in the development of T2DM: Asians have a higher burden of diabetes and prediabetes at lower BMI than non-Asians [38]. There are two potential reasons for the burden of diabetes in Asians. First, Asians have a low capacity for insulin secretion [39], [40]. In a Korean cohort study, patients who progressed to diabetes had lower baseline insulin secretory capacity without a compensatory increase in response to lower insulin sensitivity at diabetes onset than non-diabetic controls [39], [40], [41]. Second, Asians are genetically predisposed to insulin resistance because they have a greater predisposition to visceral adiposity at a lower BMI presumably through a lower capacity for storage in the subcutaneous fat than non-Asians [42], [43]. These may explain at least partly a much greater propensity for cardiometabolic disorders in Asians [43].

Of note, the classification of T2DM into two types is convenient for clinical use (Fig. 1B). It should be emphasised that there are significant differences in the degree of insulin resistance and diabetic complications within obese (MHO vs. MUO) and lean diabetes. In the lipodystrophic phenotype, the risk of developing diabetes is high, even in cases of extreme leanness [24], [36], [44]. An accumulation of ectopic fat in the liver and the skeletal muscle caused by a low lipogenic capacity of the subcutaneous fat results in severe insulin resistance, resembling the risk of complications in severely obese patients with T2DM (Fig. 1B) [24], [36], [44].

Sub-classification of adult-onset diabetes mellitus based on cluster analysis discussed above, Ahlqvist et al. reported five exclusive subgroups for diabetes: cluster 1 (severe autoimmune diabetes [SAID]), cluster 2 (severe insulin-deficient diabetes [SIDD]), cluster 3 (severe insulin-resistant diabetes [SIRD]), cluster 4 (mild obesity-related diabetes [MOD]), and cluster 5 (mild age-related diabetes [MARD]) [13]. This classification is more comprehensive than the classical classification, i.e., T1DM and T2DM [1], [2], because it appraises obesity, aging, autoimmunity, insulin secretory capacity, and insulin resistance [18]. T2DM can be classified into two subtypes in clinical practice: obese insulin resistance and lean insulin deficiency. However, the former does not consider the concept of MHO and MUO, while the latter inadequately predicts the risk of non-obese insulin resistance, especially in Asians. Meanwhile, the newly identified Ahlqvist classification, which subdivides obesity into metabolically healthy and unhealthy, allows for a better assessment of complication risk.

One could claim that diabetic patients migrate between clusters with long duration of diabetes [45]. However, it is considered that individuals are phenotyped before the onset of diabetes and do not migrate between clusters, even with the progression of disease duration [15], [46]. Cluster was a risk factor for diabetic complications independent of the duration of diabetes [17]. Collectively, the cluster classification may predict diabetic complications from the early to late phase of the diabetes time course, independent of the duration of diabetes treatment. However, this notion should be evaluated also in future studies. Here we briefly discuss the clinical phenotypes of the five subgroups.

Cluster 1: SAID The SAID cluster, defined by the presence of GADA, includes individuals with multiple autoantibodies. Therefore, SAID is acute-onset or LADA [18]/SPIDDM [21], but not fulminant, which tests negative for autoantibodies [22]. There is debate as to whether slowly progressive autoimmune diabetes with adult-onset should be termed T1DM. However, the use of the term LADA [18]/SPIDDM [21] is common and acceptable in clinical practice. It has the practical impact of increasing awareness of a population of adults likely to develop overt autoimmune β-cell destruction [1]. Three distinct stages of autoimmune T1DM have been proposed by considering methods of autoantibody detection: stage 1, autoantibodies plus normoglycaemia; stage 2, autoantibodies plus asymptomatic dysglycaemia; and stage 3, autoantibodies plus symptomatic hyperglycaemia [3]. The SAID nomenclature is in line with this staging to optimise the diagnosis and therapeutic strategy of autoimmune diabetes under the rubric of T1DM. Regardless of age groups at onset and rate of progression before symptomatic hyperglycaemia, acute-onset vs. LADA/SPIDDM, SAID is associated with low or depleted insulin secretory capacity, low BMI, and poor glycaemic control (high A1c level) [18]; thus, there is a risk of ketoacidosis [47]. SAID features the highest prevalence and incidence of diabetic retinopathy [17], [18] and a risk of fracture [48].

Cluster 2: SIDD The SIDD cluster shows clinical profiles similar to those of SAID except for GADA positivity [18]. SIDD features a mildly to severely low insulin secretory capacity and low BMI and develops at a relatively older age than SAID. There is also poor glycaemic control (high A1c level) [18] and, thus, the risk of ketoacidosis [47] although its frequency is lower than that in SAID. SIDD has a higher prevalence and incidence of diabetic retinopathy and neuropathy [17], [18] and may confer a fracture risk [48]. There are conflicting reports on whether the frequency of SIDD differs among Caucasians [13], [14], [15], South Asians [49], and East Asians [17], [50]; this topic requires future evaluation. Ketosis-prone diabetes is a unique form of diabetes mellitus, namely intermediate between T1DM and T2DM, and may be related to SIDD [51

Cluster 3: SIRD The SIRD cluster shows obesity and moderate to severe insulin resistance with hyperinsulinemia. Glycaemic control is relatively mild (low A1c level). Under severe metabolic deterioration based on insulin resistance through ectopic fat accumulation [24], [25], [26], [27], individuals with SIRD are at high risk of developing ASCVD. SIRD confers the highest risk of developing DKD, commonly in Caucasians [18] and non-Caucasians [17]. Since insulin resistance and hyperinsulinemia are associated with the onset and progression of cancer and dementia (Alzheimer's disease) [52], [53], SIRD may also carry the risk of cancer and dementia. The frequency of this cluster is not consistent within Asians, as it was slightly lower in Japan [17] but higher in India [49] and China [50].

Cluster 4: MOD The MOD cluster shows a high BMI and mild to moderate insulin resistance. Obesity may be linked to the onset of MOD to a lesser extent than SIRD. Glycaemic control is relatively good, and somewhat fewer micro- and macrovascular complications are involved than with other clusters. MOD resembles MHO [54], [55] and has a lower prevalence of obesity-related complications such as hypertension, dyslipidaemia, and NAFLD [56] than SIRD.

Cluster 5: MARD MARD has elderly-onset diabetes but no other clinical characteristics. This cluster is the largest among Caucasians [13], [15] and Asians [17], [50]. Age-related decreases in insulin secretory capacity and insulin sensitivity, which are generally caused by changes in body composition with decreased muscle mass and relatively increased fat mass [57], are the suspected main causes of MARD. Glycaemic control is good, and there were few microangiopathies. In elderly MARD individuals, attention should be paid to senile syndromes such as frailty syndrome, mild cognitive impairment, osteoporosis and fracture, and ASCVD [45].

Therapeutic strategies for managing glycaemic control and preventing diabetic complications The basic strategies for glycaemic control in adult-onset diabetes mellitus depend on the type, condition, age, and degree of complications of diabetes and metabolic disorders [7], [8], [9], [10]. In the current guidelines, metformin and comprehensive lifestyle managements are recommended as the first-line therapy for T2DM [7], [8], [58]. The choice of antidiabetic drug classes is based on ASCVD, hypoglycaemic risk, weight effects, cost, and patient preferences [7], [8], [9], [58]. This recommendation is mainly based on evidence from clinical trials, but these statements do not fully consider the patients’ pathophysiological background. In other words, currently proposed therapeutic strategies remain limited as a regimen tailored to the pathology of T2DM [59] in which responsiveness to the different classes of antidiabetic agents varies from person to person.

In addition to the above evidence-based approach, a therapeutic strategy based on the pathophysiological background is intriguing. Here we proposed a five-step approach of non-pharmacological and pharmacological treatments based on the pathophysiology of obesity-related insulin resistance or low insulin secretory capacity in adult-onset diabetes mellitus (Fig. 3). To pursue a more integrated strategy, we performed two-dimensional phenotypic mapping of diabetic complications and commodities for the five clusters (Fig. 4). Here we discuss its possible therapeutic utilities.

Five-step approach for the non-pharmacological and pharmacological treatment of adult-onset diabetes mellitus based on the pathophysiology of obesity-related insulin resistance or low insulin secretory capacity. Adult-onset diabetes mellitus is classified into types with obesity-related insulin resistance or with low insulin secretory capacity. Obesity-related insulin resistance is strongly linked to visceral fat obesity and ectopic fat disposition [44], [63]. Free fatty acids in visceral fat are delivered to remote organs such as the pancreas [32], [44], liver, skeletal muscle, and kidney and are a crucial fuel for satisfying metabolic demands, but they are accumulated when delivered more than required (ectopic fat accumulation) [44], [63]. Ectopic fat accumulation is a main cause of insulin resistance, a phenomenon known as lipotoxicity [

induces organ dysfunction and complications in the β-cells (by pancreas fat) [31], [32], the liver (by liver fat) [90], the skeletal muscle (by muscle fat) [25], [26], [27], the kidney (by kidney fat) [100] and the cardiovascular system (by cardiac fat: epicardial and perivascular fat) [24]. The red colour indicates the accumulations of ectopic fat and visceral fat. We introduce a simple method for assessing pathophysiology in treating patients with diabetes based on the presence and absence of accumulation of visceral fat and ectopic fat. Step 1: estimate the pathophysiological conditions (yes or no visceral fat and ectopic fat); in patients with no ectopic and visceral fat, consider insulin deficiency caused by β-cell failure (blue colour);

Step 2: determine optimal A1c targets according to the guidelines [7], [8], [9], [10]; Step 3: set optimal body weight targets. For the body weight target, it is crucial to assess the degree of visceral and ectopic fat accumulation, not the total body weight which includes lean body mass such as the skeletal muscle. When visceral and ectopic fat accumulation is linked to insulin resistance and hyperglycaemia, it should be reduced. When visceral and ectopic fat is not accumulated, current body weight should not be reduced;

Step 4: prescribe diet and exercise to achieve optimal A1c and body weight targets; Step 5: Select the optimal class of antidiabetic agents when optimal A1c targets are not achieved in Step 3. While choosing an optimal class of antidiabetic agents, target organs (β-cells vs. the liver, the skeletal muscle, and visceral and ectopic fat) should be considered. The blue box represents the classes of drugs that act on β-cells and stimulate insulin secretion or compensate for insulin demands. The red box represents the classes of drugs linked to reduction or modulations in visceral and ectopic fat. FFA: free fatty acid, SGLT2i: sodium glucose cotransporter 2 inhibitors, TZD: thiazolidinedione, GLP1RA: GLP1 receptor agonist, DPP4i: dipeptidyl peptidase-4 inhibitor, α-Gi: α-glucosidase inhibitor, TG: triglycerides, HDL-C: high density lipoprotein cholesterol, DKD: diabetic kidney disease, ASCVD: atherosclerotic cardiovascular disease, AF: atrial fibrillation. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article

Two-dimensional phenotypic mapping for diabetic complications and commodities and potential therapeutic strategies among the five clusters of adult-onset diabetes mellitus. According to the cluster analysis, adult-onset diabetes is categorized as severe autoimmune diabetes (SAID, cluster 1), severe insulin-deficient diabetes (SIDD, cluster 2), severe insulin-resistant diabetes (SIRD, cluster 3), mild obesity-related diabetes (MOD, cluster 4), and mild age-related diabetes (MARD, cluster 5). The five clusters are then placed on the map with the two axes representing insulin secretory capacity and insulin resistance. The characteristic phenotypes of diabetic complications including retinopathy, diabetic kidney disease (DKD) and neuropathy and ketoacidosis, and the comorbidities including non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), atherosclerotic cardiovascular disease (ASCVD)/heart failure/atrial fibrillation (AF), frail, fracture, and mild cognitive impairment (MCI) are shown. Therapeutic issues, including glycaemic control and other risk factors and related treatment procedures are also placed. SGLT2i: sodium glucose cotransporter 2 inhibitors, TZD: thiazolidinedione, GLP1RA: GL

Noval classification of diabetes mellitus