Etiology
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Diabetes Mellitus Type 2Published by: Domus Medica | SSMGLast published: 2017Diabète sucré de type 2Published by: SSMG | Domus MedicaLast published: 2017Type 2 diabetes often presents on a background genetic predisposition and is characterized by insulin resistance and relative insulin deficiency. Insulin resistance is aggravated by aging, physical inactivity, and overweight (body mass index [BMI] 25.0 to 29.9 kg/m²) or obesity (BMI >30 kg/m²).[35] Among patients with obesity, weight loss often reduces the degree of insulin resistance and may delay diabetes onset or ameliorate its severity, thereby reducing the risk of long-term complications. Insulin resistance affects primarily the liver, muscle, and adipocytes, and is characterized by complex derangements in cellular receptors, intracellular glucose kinase function, and other intracellular metabolic processes.[5] The complexity and variety of these intracellular derangements suggest that what is now classified as type 2 diabetes may be, in fact, a larger group of conditions that await future definition.
Pathophysiology
In type 2 diabetes, insufficient levels of insulin fail to meet the elevated demand caused by increased insulin resistance.[13] Adaptive changes in beta-cell mass and beta-cell function typically allow the regulation of insulin demand during insulin resistance. If functional beta-cell compensation becomes insufficient, a cycle of incomplete glucose clearance and subsequent elevated blood glucose contributes to further deterioration of beta-cell mass and function. The increased beta-cell workload results in functional exhaustion, possible dedifferentiation, and, finally, beta-cell death.[13] Beta-cell function is estimated to be decreased by about 50% to 80% at the time of diagnosis of type 2 diabetes, and protection and recovery of beta-cell function should be a main treatment and prevention target.[13]
The brain is increasingly recognized as a key contributor to the pathophysiology of type 2 diabetes. Specialized glucose-sensing neurons, predominantly located within the hypothalamus and brainstem, monitor peripheral glycemia and orchestrate systemic glucose homeostasis via modulation of insulin secretion and hepatic glucose output.[36] Disturbances within these central pathways, including impaired cerebral insulin signaling and aberrant neuronal responses to glucose, are implicated in the dysregulation of peripheral glucose metabolism characteristic of the disease.[37] Early pharmacologic intervention targeting these disturbances holds promise for the treatment and prevention of type 2 diabetes.[37]
Disruption of the gut microbiome has also been postulated to play an important role in the development of various obesity-related metabolic abnormalities, among them type 2 diabetes and cardiovascular disease (CVD). The intestinal microbiota may therefore be a promising target for the nutritional or therapeutic management of these diseases.[38]
Vascular complications are the major cause of morbidity and mortality in people living with diabetes. These result from interactions between systemic metabolic abnormalities, such as hyperglycemia, dyslipidemia, genetic and epigenetic modulators, and local tissue responses to toxic metabolites.[39] However, the precise mechanism by which the diabetic metabolic state leads to microvascular and macrovascular complications is only partly understood, with research suggesting that multiple biochemical pathways link the adverse effects of hyperglycemia with vascular complications.[39] Cellular mechanisms include: nonenzymatic glycation and the formation of advanced glycation end products; enhanced reactive oxygen production and actions; endoplasmic reticulum stress; and the activation of the polyol pathway, the diacylglycerol (DAG)-protein kinase C (PKC) pathway, Src homology-2 domain-containing phosphatase-1 (SHP-1), and the renin-angiotensin system and kallikrein-bradykinin systems.[39] It is likely that hyperglycemia-induced intracellular and extracellular changes alter signal transduction pathways, thus affecting gene expression and protein function and causing cellular dysfunction and damage.[39]
Due to the overlap in pathophysiology between diabetes, CVD, obesity, and chronic kidney disease (CKD), some groups argue that these conditions should be considered to be on a single spectrum known as cardiovascular-kidney-metabolic (CKM) syndrome. The American Heart Association, notably, has endorsed this terminology and proposed a four-stage model based on a patient’s number of risk factors and the presence of overt CVD.[40] It has also developed a series of risk prediction equations, known as PREVENT, for estimating 10- and 30-year CVD risks based on the CKM concept.[41] It is hoped that this new approach will improve screening, prevention, and treatment of CKM risk factors, particularly in people with adverse social determinants of health.[40]
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