Diabetes Mellitus Disease Background

Introduction

Diabetes mellitus (DM) is a heterogeneous metabolic disorder characterized by the presence of hyperglycemia with carbohydrate, protein, and fat metabolism disturbance which results from defects in either insulin secretion or action or both.

Epidemiology

In 2021, approximately 537 million adults worldwide are diagnosed with diabetes, and it is projected to rise to 643 million by 2030 and 783 million by 2045. Type 2 diabetes mellitus accounts for 90-95% of diabetes.  

Western Pacific countries account for 38% of cases (206 million) in 2021 and are projected to rise to 238 million cases and 260 million cases by 2030 and 2045, respectively. Australia and New Zealand have 1.4 million and 268,000 cases, respectively, in 2021. China has 140 million cases in 2021. Hong Kong has 686,000 cases in 2021. Indonesia has 19 million cases in 2021. Japan has 11 million cases in 2021. Malaysia has 4.4 million cases in 2021. The Philippines has 4.3 million cases in 2021. Singapore has 711,000 cases in 2021. Thailand has 6.07 million cases in 2021. Vietnam has 3.9 million cases in 2021. South-East Asian countries account for 90 million cases in 2021 and are projected to rise to 113 million cases and 152 million cases by 2030 and 2045, respectively. India has 74.2 million cases in 2021.

Pathophysiology

Diabetes mellitus is a heterogeneous disease caused by defective insulin secretion and action. Genetic and environmental factors (eg family history, diet, physical activity) play a role in the pathogenesis of diabetes mellitus.  

Insulin resistance is implicated in other conditions associated with diabetes mellitus (ie inflammation, lipoprotein abnormalities, hypertension, obesity). It is primarily exhibited as decreased insulin-stimulated glucose transport and metabolism in skeletal muscles, impaired insulin suppression of lipolysis, and impaired ability of insulin to inhibit hepatic glucose output. Hyperinsulinemia has been shown to cause insulin resistance through the downregulation of insulin receptors and desensitization of post-receptor pathways.  

In vivo, chronic activation of the insulin receptor from hyperinsulinemia impairs insulin signaling via feedback inhibition through:

• Serine phosphorylation of insulin receptor substrate (IRS) increases ubiquitination and degradation of IRS isoforms resulting in decreased insulin signaling
• Signaling via mTOR increases Grb10 and Grb14 which are negative regulators of insulin signaling
• Insulin-mediated mitogen-activated protein kinase (MAPK) activation results in the activation of extracellular signal-regulated kinase (ERK) which inhibits IRS function
• FoxO transcription factors regulate the transcription of insulin receptors and other inhibitors of Akt action (eg Trb3 and protein phosphatase 2A)

The development of insulin resistance has also been shown to be associated with the decreased ability of the insulin receptor to autophosphorylate and the increased activity of the protein tyrosine phosphatases, PTP1B and LAR.  

Impaired insulin processing is postulated to be involved in the pathogenesis of diabetes mellitus. Studies have shown an increase in proinsulin secretion in patients which is suggestive of decreased conversion of proinsulin to insulin reflective of beta cell dysfunction, and insufficient time for the granules to properly mature before the release of proinsulin.

Etiology

Various genetic and environmental factors can cause progressive loss of β-cell mass and/or function that manifests clinically as hyperglycemia in both types 1 and 2 diabetes mellitus. When hyperglycemia occurs, patients with both type 1 and 2 diabetes mellitus are at risk of developing the same complications but with different rates of occurrence and progression. Better characterization of the many paths to β-cell dysfunction is required in the identification of individualized therapies for diabetes mellitus.

Classification

Diabetes mellitus can be classified as type 1, type 2, gestational, and other specific types.  

Type 1 Diabetes Mellitus  

Type 1 diabetes mellitus constitutes 5-10% of patients with diabetes. Patients are usually <35 years of age, with personal or family history of autoimmune or polyglandular autoimmune syndromes, body mass index (BMI) of <25 kg/ m², family history of type 1 diabetes mellitus, inadequate glucose control on non-insulin therapies and presence of comorbidities (eg history of cancer treatment with immune checkpoint inhibitors). It is caused by β-cell destruction which leads to complete insulin secretion deficiency which may be immune-mediated or idiopathic.  

Immune-mediated type 1 diabetes mellitus occurs more commonly in childhood or adolescence but may occur at any age. The persistence of autoimmune markers like islet cell antibodies (ICA) or other islet autoantibodies (eg antibodies to glutamic acid decarboxylase [GAD] 65, insulin, anti-tyrosine phosphatase-related islet antigen 2 [anti-IA-2] and IA-2 beta, and zinc transporter ZnT8) in serum may help establish the diagnosis of type 1 diabetes mellitus.  

Type 2 Diabetes Mellitus  

Type 2 diabetes mellitus is the most common form of diabetes (90% of diabetes population). It is secondary to the progressive loss of β-cell insulin secretion concomitant with insulin resistance. The insulin secretory defects are related to inflammation, metabolic stress, and genetic factors. This type of diabetes usually presents in patients >30 years old who are overweight or obese or with a BMI of ≥25 kg/m², without weight loss and/or have a positive family history. It does not have autoantibodies.  

Gestational Diabetes Mellitus *  

Gestational diabetes mellitus is diabetes diagnosed during pregnancy (second and third trimester) that was not present prior to gestation.  

*Please see Gestational Diabetes Mellitus disease management chart for further information.  

Other Types of Diabetes Mellitus  

There are other specific types of diabetes mellitus. These are uncommon causes of diabetes wherein an underlying problem or disease process is identified. Examples include genetic defects in β-cell function and insulin action, diseases of the exocrine pancreas, or secondary to drug or chemical use.  

Monogenic diabetes syndrome (eg neonatal diabetes, maturity-onset diabetes of the young) is suggested by the presence of ≥1 of the following: HbA1c <7.5% (<58 mmol/mol) at diagnosis, one parent with diabetes, features of a specific monogenic cause (eg maternally inherited deafness, partial lipodystrophy, renal cysts, severe insulin resistance in those without obesity) and monogenic diabetes prediction model probability of >5%.