Lili Indrawati

Treatment algorithm for management of type 2 diabetes

mellitus.
Patients diagnosed with type 2 diabetes, either by fasting glucose,
oral glucose tolerance testing, or A1C, should have diabetes
education that includes instruction on medical nutrition therapy
and physical activity.

Treatment algorithm for management of type 2

diabetes mellitus
Most patients newly diagnosed with type 2
diabetes have had subclinical or undiagnosed
diabetes for many years previously

and
should be evaluated for diabetic complications
(retinal exam, test for excess protein or albumin
excretion in the urine, and clinical evaluation for
peripheral neuropathy and vascular insufficiency);
common comorbidities (hypertension and
dyslipidemia) should be treated.

 Metformin is the consensus first line of therapy and should

be started at the time of diagnosis.

Failure to reach the glycemic target, generally a A1C 7%
within 3-4 months, should prompt the addition of a second
oral agent.
Reinforce lifestyle interventions at every visit and check
A1C every 3 months.
Treatment may escalate to metformin plus two oral agents
or metformin plus insulin, if necessary

Sulphonylurea
The sulphonylureas (r) and repaglinide close KATP
channels (middle), causing depolarization of the
-cells and increased insulin release.

Sulphonylurea
The increased release of insulin continues while
there is ongoing drug stimulation, provided the
cells are fully functional.
Sulphonylureas can cause hypoglycaemia since
insulin release is initiated even when glucose
concentrations are below the normal threshold for
glucose-stimulated insulin release (approximately

5 mmol/L).

Sulphonylurea
Sulphonylureas are indicated in patients (especially

those near their ideal weight) in whom diet fails to

control the hyperglycaemia, but in about 30% control
is not achieved with these drugs.
These agents stimulate insulin release from the
pancreatic islets and so the patient must have partially
functional -cells for these drugs to be of use.

Sulphonylurea
Glipizide and glicazide have relatively short halflifes and are commonly tried flrst.
Glibenclamide has a longer duration of action and
can be given once daily.
However, there is more chance of hypoglycaemia
and glibenclamide should be avoided in patients at
risk from hypoglycaemia (e.g. the elderly). These
patients may be more safety given tolbutamide,
which has the shortest duration of action.

Biguanide

glycogenolysis

Fig. 4. Actions of
metformin.
lnhibition of hepatic
glucose production is
regarded as the
principal mechanism
through which
metformin lowers
blood glucose
FA = fatty acids

Mode of Action
Metformin has a variety of metabolic effects, some of

which may confer clinical benefits that extend beyond

glucose lowering (table V). However, the molecular
mechanisms of metformin have yet to be fully identified.
At the cellular level, metformin improves insulin
sensitivity to some extent, an action mediated via postreceptor signalling pathways for insulin.

 Recent data have suggested that adenosine 5'monophosphate-activated protein kinase (AMPK)
is a possible intracellular target of metformin.
Through phosphorylation of key proteins, AMPK
acts as a regulator of glucose and lipid metabolism
and cellular energy regulation.

 Since metformin lowers blood glucose concentrations

without causing overt hypoglycaemia it is most

appropriately classed as an anti-hyperglycaemic as
distinct from hypoglycaemic - agent.
The clinical efficacy of metformin in patients with type 2
diabetes requires the presence of insulin.
The drug does not stimulate insulin release and a small
decrease in fasting insulin concentrations is typically
observed in patients with hyperinsulinaemia.

 The predominant glucose-lowering mechanism of action of

metformin is to reduce excessive rates of hepatic glucose

production.
Metformin reduces gluconeogenesis by increasing hepatic
sensitivity to insulin and decreasing the hepatic extraction
of certain gluconeogenic substrates (e.g. lactate).

 Hepatic glycogenolysis is also decreased by

metformin.
Insulin-stimulated glucose uptake in skeletal muscle
is enhanced by metformin increase in the activity of
the enzyme glycogen synthase promotes synthesis of
glycogen.

 Metformin also acts in an insulin-independent

manner to suppress oxidation of fatty acids and to

reduce triglyceride levels in patients with
hypertriglyceridaemia.

 This reduces the energy supply for hepatic

gluconeogenesis and has favourable effects on the
glucose-fatty acid (Randle) cycle (in which fatty
acids are held to compete with glucose as a cellular

energy source).
Glucose metabolism in the splanchnic bed is
increased by metformin through insulinindependent mechanisms. This may contribute to
the blood glucose-lowering effect of the drug, and
in turn may help to prevent gains in bodyweight.

 Collectively the cellular effects of metformin serve

to counter insulin resistance and to reduce the
putative toxic metabolic effects of hyperglycaemia
(glucose toxicity) and fatty acids (lipotoxicity) in
type 2 diabetes.

Metabolic and vascular effects of metformin

Antihyperglicemic action
suppresses hepatic glucose output
increases insulin-mediated glucose utilisation
decreases fatty acid oxidation
increases splanchnic glucose turnover
Weight stabilisation or reduction
lmproves lipid profile
reduces hypertriglyceridaemia
lowers plasma fatty acids and LDl-cholesterol; raises HDLcholesterol
in some patients

No risk of serious hypoglycaemia

Counters insulin resistance
decreases endogenous or exogenous insulin requirements
reduces basal plasma insulin concentrations
Vascular effects
increased fibrinolysis
decreases PAI-I levels
improved endothelial function
l19L = hign-density lipoprotein; LDL = low-density lipoprotein;
PAI-1 = plasminogen activator inhibitor-1.

Pharmacokinetics
Metformin is a stable hydrophilic biguanide that is quickly

absorbed and eliminated unchanged in the urine.

It is imperative that metformin is only prescribed to
patients with renal function that is sufficient to avoid
accumulation of the drug.
Renal clearance of metformin is achieved more by tubular
secretion than glomerular filtration, the only significant
drug interaction being competition with cimetidine,
which can increase plasma metformin concentrations.

Thiazolidinedione

Mechanism of action or a thiazolidinedione on an adipocyte

aP2 = adipocyte fatty acid protein; CoA = coenzym A, FATP= fatty acid
transporter protein; GLUT4 = glucose transporter-4; PPAR= peroxisome
proliferator-activated receptor-; RxR = rerinoid X receptor; vLDL = very lowdensity lipoprotein

Mode of Action
Stimulation of PPAR is regarded as the principal
mechanism through which thiazolidinediones
enhance insulin sensitivity.
PPAR is expressed at highest levels in adipose
tissue, and less so in muscle and liver.

Mode of Action
PPAR operates in association with the retinoid X receptor.

The resulting heterodimer binds to nuclear response

elements, thereby modulating transcription of a range of
insulin-sensitive genes, in the presence of necessary
cofactors

Mode of Action
Many of the genes activated or suppressed by

thiazolidinediones are involved in lipid and carbohydrate

metabolism (table VI). Stimulation of PPARy by a
thiazolidinedione promotes differentiation of preadipocytes with accompanying lipogenesis, effects that
promote or enhance the local effects of insulin.
Thiazolidinediones increase glucose uptake via glucose
transporter-4 in skeletal muscle, and some reports
indicate that rates of gluconeogenesis in the liver are
reduced.
Stimulation of lipogenesis via PPAR reduces circulating
non-esterified fatty acid (NEFA) concentrations through
cellular uptake and triglyceride synthesis

Mode of Action
The reduction in plasma NEFA concentrations is

associated with increased glucose utilisation &

reducing gluconeogenesis by reducing operation of the
glucose-fatty acid cycle; reductions in ectopic lipid
deposition in muscle and liver may contribute to the
improvements on glucose metabolism.
Thiazolidinediones also reduce the production and
activity of the adipocyte-derived cytokine tumour
necrosis factor (TNF)- has been implicated in the
development of impaired insulin action in muscle

.
The glitazones improve sensitivity to insulin.Type II

diabetics not controlled by diet and oral antidiaberic drugs

require insulin injdctions.

-Glucosidase lnhibitors

-Glucosidase lnhibitors
The -glucosidase inhibitors competitively inhibit the

activity of -glucosidase enzymes in the brush border of

enterocytes lining the intestinal villi (figure 3).
High affinity binding prevents these enzymes from
cleaving their normal disaccharide and oligosaccharide
substrates into monosaccharides prior to absorption.
This defers the completion of carbohydrate digestion until
further along the intestinal tract, in turn causing glucose
absorption to be delayed.

-Glucosidase lnhibitors
The -glucosidase inhibitors should be taken with meals

containing digestible carbohydrates, not

monosaccharides; these drugs generally do not
significantly affect the absorption of glucose.
Since -glucosidase inhibitors move glucose absorption
more distally along the intestinal tract they alter glucosedependent release of intestinal hormones that enhance
nutrient-induced insulin secretion.

-Glucosidase lnhibitors
Release of gastric inhibitory polypeptide, which

occurs mainly from the jejunal mocosa, may be

reduced by -glucosidase inhibitors, whereas
glucagon like peptide-l (7-36 amide) secretion (mostly
from the ileal mucosa) is increased.
Overall, -glucosidase inhibitors reduce postprandial
insulin concentrations through the attenuated rise in
postprandial glucose levels.

Pharmacokinetics
Acarbose is absorbed only to a trivial degree (<2%).
The drug is degraded by amylases in the small

intestine and by intestinal bacteria; some of these

degradation products are systemically absorbed,
subsequently to be eliminated in the urine over about
24 hours.

Adverse effects
Gastrointestinal disturbances and rashes occur, but are

rare.
Hypoglycaemia and hypoglycaemic coma may be induced
by longer-acting drugs, especially in elderly patienrs.
Sulphonylureas are contraindicated in severe (especially
ketotic) hyperglycaemia, surgery and major illness, when
insulin should be given.

Adverse effects
Repaglinide is a benzamido derivative with a rapid onset

and short duration of action. It is taken at the onset of a

meal to provide a surge of insulin release during digestion
with a reduced risk of interprandial hypoglycaemia.
Biguanides. Metformin acts peripherally to increase
glucose uptake by an unknown mechanism. As it does not
increase insulin release, it rarely causes hypoglycaemia.
Adverse effects include nausea, vomiting, diarrhoea and,
very occasionally, fatal lactic acidosis.

Adverse effects
Acarbose inhibits intestinal -glycosidases, delaying the

digestion of starch and sucrose. It is taken with meals and

lowers the postprandial increase of blood glucose. Its main
side-effect is flatulence.
Glitazones (thiazolidinediones). These new drugs increase
sensitivity to insulin by binding to the nuclear ppAR-
recepror and. By derepression, increase transcription of
certain insulin-sensitive gcncs.
They are given in combination with metformin or
sulphonylureas.
The glitazones have no demonstrated advantages over
older therapies and their long-term safety is unknown.

References
Andrew J. Krentz1 and Clifford J. Bailey. Oral

Antidiabetic Agents Current Role in Type 2

Diabetes Mellitus. Drugs 2005; 65 (3): 385-411
Goodman and Gilmans 12th ed
Pharmagology at a glance