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Epidemiology and impact of hypoglycaemia in type 2
diabetes and CKD

In patients with advanced type 2 diabetes, such as those with CKD, the
incidence and severity of hypoglycaemia are high. Severe hypo-
glycaemia (requiring medical attention) probably occurs at a rate of
about 50 episodes per 100 patient-years. These rates are at least 5-10
fold higher than observed in diabetic patients without CKD. Mild and/
or asymptomatic hypoglycaemic events are even more common, and
possibly ubiquitous. Data from small studies using continuous glucose
monitoring in diabetic patients on dialysis reveal a glimpse of the size of
the potential problem. For example, in a recent study of nine diabetic
patients undergoing haemodialysis, ten hypoglycaemic events were
seen in five subjects over a two-day monitoring period. Only three
4
episodes were associated with symptoms and confirmed by capillary
blood glucose tests. 4
Individuals experiencing hypoglycaemia have an increased risk of ad-
verse outcomes. This is not simply severe symptomatic events or deaths
due to neuroglycopaenia. In fact, all-cause mortality is increased in
those with a higher incidence of hypoglycaemia. It is possible that
5
hypoglycaemia is simply a marker of vulnerability to such events. How-
ever, some data suggest that hypoglycaemia may directly contribute to
adverse outcomes. For example, the surge of sympathetic activity and a
release of catecholamines associated with hypoglycaemia has been
associated with cardiovascular events, arrhythmia and sudden death. 7
6

Renal gluconeogenesis

Although the liver is generally regarded as the seat of gluconeogen-
esis, healthy kidneys also synthesise and release significant quantities
of glucose into the circulation , the loss of which also contributes to hy-
8
poglycaemia in patients with CKD. Following overnight fasting, approx-
imately half of all glucose released comes from gluconeogenesis, with
the other half coming from hepatic glycogenolysis (Figure 2). The liver
8
and the kidney are the only two organs capable of gluconeogenesis in
the human body. The liver is the major contributor to gluconeogenesis
in healthy individuals (~60% of all gluconeogenesis following overnight
fasting). However, glucose levels are maintained even in the absence
of liver tissue (e.g. after removal of the liver in individuals undergoing
liver transplantation), with overall endogenous glucose release only
falling by less than 50%. It is now thought that hormonally regulated gluco-
neogenesis in the renal cortex accounts for ~20% of all glucose pro-
duced following overnight fasting (40% of all gluconeogenic sugar). 9, 10

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