Insulin resistance may occur independently of inadequate insulin secretion and be a prerequisite for incident type 2 diabetes. The direct evidence for a time- dependent association between insulin sensitivity and deterioration of glucose tolerance preceding type 2 diabetes comes from comparison of population trajectories of fasting and post- glucose challenge plasma glucose concentrations with HOMA- S and insulin secretion (HOMA- B) in people developing or remaining free of diabetes in the longitudinal Whitehall II study. This study found that individuals had 29% lower HOMA- S but 13% greater HOMA- B values at 13 years before the onset of diabetes. HOMA- S decreased linearly until about five years before diagnosis and with an even steeper slope during the last five years prior to diagnosis. Thus, insulin resistance represents an early abnormality, which is compensated by augmented β- cell function for a long time before the insulin–glucose feedback loop fails. Insulin resistance not only predicts type 2 diabetes, but also correlates with cardiovascular disease and outcomes.

The most important factors predicting type 2 diabetes are male sex, increasing age, overweight, and obesity [26]. Insulin resistance is frequent in people with the so- called metabolic syndrome, which, in addition to visceral obesity, comprises dyslipidaemia, hypertension, and dysglycaemia. Hyperuricaemia, arteriosclerosis, microalbuminuria, platelet hyperaggregation, and antifibrinolysis, sleep apnoea, and male hypogonadism have also been associated with this syndrome. The risk of type 2 diabetes is also markedly higher in first- degree relatives of individuals with type 2 diabetes and in women with a history of gestational diabetes mellitus or polycystic ovary syndrome, all of whom are mostly insulin resistant. These associations raise the question of whether chronic insulin resistance represents an inherited or an acquired abnormality. Despite the fact that a family history of type 2 diabetes raises the risk of type 2 diabetes in relatives, even the combination of all currently known genes associated with diabetes adds little to the pre diction of type 2 diabetes based on sex, age, and body mass index. Marked differences exist at the clinical onset of diabetes: clustering based on five variables including HOMA- IR identified, aside from autoimmune diabetes, four endotypes of type 2 diabetes, with one characterized by severe insulin resistance. At diagnosis, this endotype also shows the most pronounced liver steatosis and low- grade inflammation, whereas the other endotypes exhibit increasing insulin resistance over the next five years.

Dietary and physical activity interventions that improve insulin resistance markedly reduce the incidence of type 2 diabetes, underscoring the predominant role of lifestyle in both the pathogenesis of insulin resistance and the progression of type 2 diabetes. Several metabolic factors related to lifestyle associate with or predict insulin resistance and type 2 diabetes. These factors are mainly related to lipid metabolism, such as plasma concentration of non- esterified fatty acids, serum triacylglyceride- to- serum high- density lipoprotein (TAG/HDL- C), and ectopic fat content in skeletal muscle (intramyocellular triacylglycerols [TAGs]) or in the liver (hepatocellular lipid content). In addition, red meat intake was among the best predictors of type 2 diabetes in a large epidemiological study and plasma concentrations of amino acids also predict type 2 diabetes.

Altered secretion patterns of cytokines, mainly derived from adipose tissue, and elevation of circulating pro- inflammatory markers such as C- reactive protein may predict insulin resistance and type 2 diabetes. Adiponectin is the only anti- inflammatory cytokine with lower circulating levels before the onset of type 2 diabetes, while concentrations of others, such as interleukin- 1 receptor antagonist (IL- 1RA), transforming growth factor β1 (TGF β1) and growth differentiation factor- 15 (GDF- 15) are increased and indicate the presence of a compensatory, but eventually futile, counter- regulation of pro- inflammatory stimuli. Although all metabolic and inflammation- related variables circulate systemically and may cause effects in several tissues simultaneously, insulin resistance may sequentially affect certain insulin- responsive tissues, such as skeletal muscle, liver, and adipose tissue.

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مواضيع ذات صلة

Stepwise development of tissue- specific insulin resistance

Insulin resistance in adipose tissue Adipose tissue

Insulin resistance in the liver

Insulin resistance in skeletal muscle

Definition and measurement of insulin resistance in humans

Hypoglycemia without Diabetes

Diabetes heterogeneity

Targeting the brain to restore normoglycaemia

Blood Glucose Regulation

Male Hypothalamic-Pituitary-Gonadal Axis

Hormone Secretion, Transport, and Clearance From the Blood

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