The skinny T2D – what do we have to watch out for?

29th October 2021, Dr Chee L Khoo

Which T2D?

Traditionally, we think of diabetes as either type 1 or type 2. That’s mainly because type 1 diabetes (T1D) was discovered first and type 2 diabetes (T2D) came later. Everything that was not T1D was T2D. T1D is an auto immune disease characterised by the death of the beta cells leading to insulin deficiency while T2D is a disease of both insulin resistance and insulin deficiency. But T2D is a heterogeneous disease. Some have more insulin resistance while others have pretty lousy beta cell reserve. The subgroups of T2D differed not only in their clinical characteristics at diagnosis but also in their pathophysiological mechanisms and susceptibility to complications.

We looked at an attempt by Scandinavian researchers to reclassify T2D patients into 5 different subgroups more than 3 years ago here. They based their classification on glutamic acid decarboxylase antibodies, age at diagnosis, HbA1c, insulin resistance levels and beta cell function. Insulin resistance and beta-cell function were assess using Homeostasis Model Assessment (HOMA2-IR & HOMA2-B). There were 5 clusters:

  1. Severe autoimmune diabetes (SAID) – Characterised by early onset disease, relatively low BMI, poor metabolic control, insulin deficiency and GADA positive
  2. Severe insulin deficient diabetes (SIDD) – Characterised by early onset disease, relatively low BMI, poor metabolic control, insulin deficiency and GADA negative
  3. Severe insulin resistance diabetes (SIRD) – Characterised by significant insulin resistance and high BMI
  4. Mild obesity-related diabetes (MOD) – Characterised by obesity but no insulin resistance
  5. Mild age-related diabetes (MARD) – Characterised by older patients but modest metabolic derangements

Indian people with T2D differ from Europeans in that they develop diabetes at a younger age and are thinner [1,2]. Indians also differ in body composition, having higher fat and lower lean proportions at the same BMI [3]. Given the role of adiposity in insulin resistance, it has, therefore, been assumed that T2D in Indians is primarily driven by insulin resistance [4]. However, it is now recognised that insulin deficiency may be the driver of diabetes in Indians [5]. Lean T2D is prevalent in India, especially in undernourished regions [6]. Younger age at diagnosis amongst Indians has significant implications for treatment, long-term complications and mortality as well as socioeconomic burden [7]. Perhaps, fitting T2D into the above subclasses may be vital for appropriate treatment to reduce adverse outcomes [8].

A recent Indian study used the Swedish algorithm to identify subgroups of young Indians with T2D diagnosed before 45 years of age from the WellGen cohort from Pune, India [9]. They compared 1612 Indians from the WellGen cohort with 962 Swedish T2D from the ANDIS cohort to obtain information on the relative distributions and characteristics in the two populations. They then allocated individuals from the WellGen study into the above clusters to assess whether clusters obtained were similar in proportion and characteristics to those from the Swedish clusters. We get to see the new proposed classification at work. This is particularly prudent considering we have increasing numbers of young T2D from the Indian subcontinent in southwest Sydney.


Compared with the Swedish ANDIS cohort, the Indian participants were:

  • Younger at diagnosis,
  • Had lower BMI,
  • Higher fasting plasma glucose and
  • Lower fasting C-peptide, HOMA2-B and HOMA2-IR (meaning lower beta cell reserves)

The proportion of participants receiving lifestyle management alone, glucose-lowering oral agents and insulin treatment was broadly similar in both cohorts.

The clusters

In the WellGen study, the SIDD cluster was the largest subgroup (52.8%), followed by the mild obesity-related MOD (37.7%), while severe insulin-resistant SIRD (1.1%) and mild age-related MARD (8.4%) were less common. As the duration of diabetes increased from < 5 years to > 5 years, the proportion of participants in the SIDD subgroup increased from 45.5% to 56.9% while that in MOD group decreased from 44.7% to 33.8%.

In the ANDIS subgroup, MOD was the most predominant cluster (67.57%), followed by SIDD (26.09%), SIRD (3.64%) and MARD (2.70%) (Fig. 1, Table 3). These distributions were similar in men and women. The pathophysiological characteristics of these Swedish individuals with young-onset type 2 diabetes were similar to those in the parent ANDIS cohort.


Expectedy, in both WellGen and ANDIS, insulin treatment (alone or in combination with OHAs) was most commonly prescribed to individuals in the SIDD subgroup (38.3% in WellGen, 51.0% in ANDIS).


Individuals in the diabetes subgroups displayed different sensitivities to micro- and macrovascular complications.

In WellGen, the prevalence of complications in the two major subtypes, SIDD and MOD were compared. Small numbers in the SIRD and MARD groups precluded comparison of complications. Retinopathy and nephropathy were most common in the SIDD subgroup whereas neuropathy was more prevalent in MOD. The prevalence of macrovascular complications was similar in these two subtypes. Of the less common subgroups, SIRD had a high prevalence of retinopathy while MARD had a high prevalence of nephropathy and macrovascular disease.

In the ANDIS cohort, nephropathy (70.4%) and retinopathy (44.4%) prevalence were highest in SIRD whereas neuropathy was most common in SIDD.

In summary, it would seem from this study that deficient insulin secretion, rather than insulin resistance, is the driver of young-onset type 2 diabetes in India. In contrast, in the young Swedish and Finnish type 2 diabetes populations, obesity and insulin resistance seemed to be the primary pathophysiological drivers. In the deficient insulin subgroup, we need to watch out for retinopathy and nephropathy. These results should influence treatment strategies for achieving optimal metabolic control. The traditional weight loss strategies may be less effective in patients with deficient insulin secretion. These patients may also require insulin therapy earlier than the usual patients with T2D.


  1. Shelgikar KM, Hockaday TD, Yajnik CS (1991) Central rather than generalized obesity is related to hyperglycaemia in Asian Indian subjects. Diabet Med 8:712–717.
  2. Yajnik CS (2001) The insulin resistance epidemic in India: fetal origins, later lifestyle, or both? Nutr Rev 59:1–9.
  3. Yajnik CS, Yudkin JS (2004) The Y-Y paradox. Lancet 363:163.
  4. Narayan KMV, Kondal D, Daya N et al (2021) Incidence and pathophysiology of diabetes in South Asian adults living in India and Pakistan compared with US blacks and whites. BMJ Open Diabetes Res Care 9:e001927.
  5. Narayan KMV, Kanaya AM (2020) Why are South Asians prone to type 2 diabetes? A hypothesis based on underexplored pathways. Diabetologia 63:1103–1109.
  6. Samal KC, Tripathy BB (1987) Malnutrition related diabetes. J Assoc Physicians India 35:170
  7. Ministry of Health and Family Welfare (MoHFW) GoI, UNICEF, (CNNS) aPCCNNS, Delhi. NRN (2016-2018) Comprehensive National Nutrition Survey. Accessed on 12 Feb 2020
  8. Golden SH, Yajnik C, Phatak S, Hanson RL, Knowler WC (2019) Racial/ethnic differences in the burden of type 2 diabetes over the life course: a focus on the USA and India. Diabetologia 62:1751–1760.
  9. Prasad, R.B., Asplund, O., Shukla, S.R. et al. Subgroups of patients with young-onset type 2 diabetes in India reveal insulin deficiency as a major driver. Diabetologia (2021).