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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%.