There are numerous causes of Type 2 diabetes, which is now known to include a wide range of disorders with differing progression and outlook. The underlying mechanism is due either to diminished insulin secretion—that is, an islet defect, associated with increased peripheral resistance to the action of insulin resulting in decreased peripheral glucose uptake, or increased hepatic glucose output. Probably as many as 98% of Type 2 diabetic patients are "idiopathic"—that is, no specific causative defect has been identified. Whether decreasing insulin secretion or increasing insulin resistance occurs first is still uncertain, but the sequence of events may vary in different individuals. Obesity is the commonest cause of insulin resistance. Other rare insulin resistant states are shown in the table.
Some adults (especially those not overweight) over 25 years of age who appear to present with Type 2 diabetes may have latent autoimmune diabetes of adulthood (LADA) and become insulin dependent. Autoantibodies are often present in this group of patients.
Type 2 diabetes is a slowly progressive disease: insulin secretion declines over several decades, resulting in an insidious deterioration of glycaemic control which becomes increasingly difficult to achieve.
Relative insulin resistance occurs in obese subjects, perhaps because of down regulation of insulin receptors due to hyperinsulinaemia. Obese subjects have a considerably increased risk of developing Type 2 diabetes. Fat distribution is relevant to the development of diabetes, so that those who are "apple shaped" (android obesity, waist-hip ratio > 0-9) are more prone to Type 2 diabetes than those who are "pear shaped" (gynoid obesity, waist-hip ratio < 0-7).
The importance of leptin in the evolution of lifestyle related obesity is unclear. Leptin is a single chain peptide produced by adipose tissue and its receptors are expressed widely throughout the brain and peripheral tissues; when injected into leptin deficient rodents it causes profound hypophagia and weight loss. Plasma leptin levels rise in parallel with body fat content. Although very rare cases of morbid obesity due to leptin deficiency have been reported, and are shown to respond to leptin injections, there is in general an absence of measurable biological responses to leptin, which at present has no role in the management of obesity.
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