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Obesity is known to be the most common cause of insulin resistance. 16
The exact relationship between the two is not fully understood, but it
is thought to involve a number of processes, involving excessive stor-
age of triglycerides in the liver (steatosis). Lipids are more abundant
19
in obese individuals and it is thought that these may interfere with the
signalling processes crucial to the correct functioning of insulin. Obes-
20
ity also triggers inflammatory responses, some of which are important in
intracellular signalling within insulin-responsive cells. Furthermore, the
20
adipose tissue is far from being an inert storage ‘depot’ (see below). 20

Figure 2. The consequences of insulin resistance. 21
β-cell dysfunction

The β-cells of the pancreas do not respond to rising glucose levels or
other stimuli that regulate insulin secretion to match the current meta-
bolic requirements. This results in a relative lack of insulin contributing
to chronic hyperglycaemia, especially in the situation of insulin resist-
ance with its higher insulin needs. In the early stages of T2DM, with
16
the advent of resistance, there is a compensatory increase in insulin
secretion in an attempt to maintain glucose and lipid homeostasis.
17
However, the time dynamics of insulin release is abnormal even at this
stage because of a reduced sensitivity of β-cells to glucose. This de-
fect is accentuated in overt T2DM. In long-standing disease, there is
usually a reduction in the islet number and/or diminished β-cell mass
in the pancreas of people with T2DM due to increased apoptosis and
inadequate regeneration. Why this should occur is not clear, but it
22
is likely to be due to a combination of genetic susceptibility and ac-
quired factors. Many β-cell ‘aggressors’ have been identified, such as
elevated glucose and free fatty acid levels (Figure 3), all of which lead
to β-cell damage and apoptosis. For example, increased levels of free
fatty acids within β-cells can inhibit proper glucose utilisation, disrupt
normal cell signalling cascades and damage mitochondria due to the
8