2.1.4 NORMAL PHYSIOLOGY
Insulin is secreted by beta cells in the
islets of Langerhans in the pancreas. When a meal is eaten, insulin
secretion increases, and moves glucose from circulation into muscle,
liver and fat cells (Gilmer et al., 2007). Insulin stimulates storage of
glucose in the liver and muscle; it also enhances storage of dietary
fat in adipose tissue and accelerates the transportation of amino acids
derived from dietary protein into cells. Insulin further inhibits the
breakdown of stored glucose, protein and fat. In normal conditions
insulin is released continuously into the blood stream (Gilmer et al.,
2007). The activity of released insulin lowers blood glucose and
facilitates a stable, normal glucose range of approximately 3.9 to
6.7mmol/l. During fasting periods (between meals and overnight) there is
a decreased release of insulin and increased release of glucagon.
Glucagon counters the effects of insulin because it stimulates the
release and breakdown of glycogen from the liver and thereby increases
blood glucose levels. The net effect of the balance between insulin and
glucagon levels is to maintain a constant level of glucose in the blood
(Gilmer et al., 2007).
2.1.5 PATHOPHYSIOLOGY OF DIABETES MELLITUS
Helseth
et al., (2009) describe the pathophysiology of type I diabetes
mellitus, which is marked by a deficiency in the production of insulin
by the pancreatic beta cells. Fasting hyperglycaemia occurs as a result
of unchecked glucose production by the liver. Glucose from food eaten
cannot be stored but remains in the blood stream and contributes to
postprandial (after-meal) hyperglycaemia (Gilmer et al., 2007). If the
concentration of glucose in the blood is high, the kidneys may reabsorb
all the filtered glucose. The glucose then appears in the urine, the
term for which is glucosuria. When excess glucose is excreted in urine
it is accompanied by excessive fluid and electrolyte loss. As a result
of the excessive loss of fluid, the patient experiences increased
urination (polyuria) and increased thirst (polydipsia) (Helseth et al.,
2009).
Insulin deficiency also impairs the metabolism of proteins
and fats, leading to loss of weight. Patients may experience an
increased appetite (polyphagia) due to decreased storage of calories.
Breakdown of stored glucose (glycogenesis) and of new glucose from amino
acids (glyconeogenesis) occurs as the insulin deficiency progresses.
These contribute further to hyperglycaemia (Helseth et al., 2009).
In
type II diabetes there are two main problems related to insulin, namely
insulin resistance and impaired insulin secretion (Mangione et al.,
2016).Insulin resistance refers to decreased sensitivity of the tissues
to insulin. Normally insulin binds to special receptors on cell
surfaces. As a result of insulin binding to these receptors, a series of
reactions involved in glucose metabolism occurs within the cell. The
insulin becomes less effective in stimulating glucose uptake by tissues
(Krishna and Boren, 2008).
Excessive secretion of insulin should take
place in order to overcome insulin resistance and to prevent the
build-up of glucose in the blood. If the beta cells fail to secrete
excessive amounts of insulin, the glucose level rises and type II
diabetes develops (Helseth et al., 2009).
2.2 TREATMENT OF DIABETES MELLITUS
2.2.1 Oral anti-diabetic drugs
Wildet
al., (2017), describe various oral anti-diabetic drugs to be used by
diabetic patients in case their blood glucose levels remain elevated in
spite of the recommended diet. There are various types of oral
anti-diabetes drugs which may include: Metformin, Diabinese, Glipizide,
Acarbose, Repaglinide, Glimepiride, Tolinase, Rezulin and Insulin.
(Polisena et al., 2009).
2.3 METFORMIN HYDROCHLORIDE
Metformin
hydrochloride, a biguanide, is the most popular oral glucose-lowering
medication in most countries, widely viewed as ‘foundation therapy’ for
individuals with newly diagnosed type 2 diabetes mellitus. This
reputation has resulted from its effective glucose-lowering abilities,
low cost, weight neutrality, overall good safety profile (especially the
lack of hypoglycaemia as an adverse effect), and modest evidence for
cardioprotection (Inzucchi et al., 2015). A derivative of guanidine,
which was initially extracted from the plant Galegaofficinalis or French
lilac, metformin was first synthesised in 1922 and introduced as a
medication in humans in 1957, after the studies of Jean Sterne (Sterne,
2007). Its popularity increased after eventual approval in the USA in
1994, although it was used extensively in Europe and other regions of
the world prior to that (Pryor and Cabreiro, 2015). The drug’s efficacy
has been demonstrated in monotherapy as well as in combination with
other glucose lowering medications for type 2 diabetes mellitus. Based
on these important characteristics, there continues to be extensive
interest in this compound, even now, many years after its incorporation
into the diabetes pharmacopeia. Interestingly, and despite this
popularity, there still remains controversy about the drug’s precise
mechanism of action, although most data point to a reduction in hepatic
glucose production being predominately involved (described further by
Rena et al in this issue of Diabetologia) (Rena et al., 2017); although,
recent data suggests that some of the drug’s effect may involve the
stimulation of intestinal release of incretin hormones. Herein, we will
review the most salient aspects of the clinical use of metformin in
individuals with type 2 diabetes mellitus.
