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The synthesis of glycogen cannot continue unabated and as the stores
of this molecule reach around 10% of the liver’s entire mass, further gly-
cogenesis is strongly suppressed and any additional glucose taken up
by the liver cells is shunted into pathways leading to the production of
fatty acids. 12 13 Once synthesised, these fatty acids are exported from
the liver as lipoproteins, which are degraded in the circulation into free
fatty acids that can be used by a number of tissues. 12 13

In addition to regulating the uptake of glucose and the synthesis of fatty
acids, insulin also promotes the accumulation of triglycerides in adipo-
cytes. Insulin facilitates the entry of glucose into adipocytes where it is
broken down to glycerol-phosphate, which esterifies fatty acids (syn-
thesised in the liver) yielding a triglyceride. 12 13

These processes highlight the importance of insulin in everything to do
with how the body stores, mobilises and utilises its energy sources. Further-
more, in regulating these process, insulin also stimulates the uptake of
amino acids, increases the permeability of many cells to potassium,
magnesium and phosphate ions, and activates sodium-potassium AT-
Pase enzymes in many cells, causing a flux of potassium into cells. 12 14

The pathophysiology of T2DM

In essence, the pathophysiological mechanisms involved in the devel-
opment of T2DM are the deterioration of β-cell function accompanied
by a reduced incretin effect, an over-activity of α-cells resulting in hyper-
glucagonaemia, and insulin resistance. Simply stating these mech-
anisms belies the true complexity of T2DM pathophysiology. We are still
a very long way from a complete understanding of the processes that
lead to the development of this disease, but with each new advance
in understanding there comes a better appreciation of how to tackle
T2DM.

Insulin resistance

Insulin resistance at the tissue level contributes significantly to hyper-
glycaemia by impeding the degree to which target cells respond to
the presence of insulin. 9 10 15-17 For example, with respect to hepatocytes
and adipocytes, insulin resistance reduces glucose uptake with a con-
sequent increase in glucose and free fatty acid output, respectively
(Figure 2). 15 16 18 Elevated levels of glucose and free fatty acids are be-
lieved to negatively impact β-cell function (discussed below), under-
lining the intimate relationship between these two pathophysiological
mechanisms.

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