**********The progression to hyperglycemia in type 2 diabetes is
characterized by a combination of relative insulin deficiency
(inadequate insulin release relative to plasma glucose levels) due
to pancreatic beta-cell dysfunction and insulin resistance
(diminished ability of insulin to stimulate glucose uptake by
skeletal muscle and unrestrained hepatic glucose output), leading
to increased blood glucose levels and hyperglycemia.1,2 As
beta-cell function progressively deteriorates, there is less
ability to compensate for increasing insulin resistance.3Ref 1, p
S5, C2, 1, L11-15
Ref 2, p 166, Table 13-1, Entry 4,C1, 1, L1-2C2, L1-5
Ref 3,p 63, 2, L1-3
ReferencesAmerican Diabetes Association. Diagnosis and
classification of diabetes mellitus. Diabetes Care 2004;27(suppl
1):S5S10.Beers MH, Berkow R, eds. Merck Manual of Diagnosis and
Therapy. 17th ed. Whitehouse Station, NJ: Merck Research
Laboratories, 1999.Williams G, Pickup JC, eds. Handbook of
Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004. Ref 1, p
S7, C1, 1, L20-29Ref 2, p 166, C1, 1, L1-2C2, L1-5p 167, C1, 3,
L4-11
**Because sulfonylureas act by increasing insulin release from
the pancreas by stimulating beta-cells, they depend on the presence
of functioning beta-cells to exert their efficacy.1,2 Dosed once or
twice daily,35 the sulfonylureas are associated commonly with
undesirable effects such as weight gain, but their main risk is
related to hypoglycemia.6
Ref 1, p 6, Fig 8 + legend,L1-9; p 7, C1, 1, L8-15Ref 2, p 2614,
C1, 2, L3-6
Ref 3,p 12, 4, L1-4Ref 4,p 8, 6, L1-2Ref 5,p 12, 2, L1-2
Ref 6, p 290C2, 3, L5-7
Ref 1, p 6, Fig 8 + legend,L1-9; p 7, C1, 1, L8-15
Ref 2, p 2614, C1, 2, L3-6
Ref 3,p 12, 4, L1-4Ref 4,p 8, 6, L1-2Ref 5,p 12, 2, L1-2
Ref 6, p 290C2, 3, L5-7
ReferencesSiconolfi-Baez L, Banerji MA, Lebovitz HE.
Characterization and significance of sulfonylurea receptors.
Diabetes Care 1990;13(suppl 3):28.Riddle MC. Oral pharmacologic
management of type 2 diabetes. Am Fam Physician
1999;60(9):26132620.Glynase prescribing information, Pharmacia
Corporation, April 2002.Glucotrol prescribing information, Pfizer,
2000.Glucotrol XL prescribing information, Pfizer, 2003.DeFronzo
RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern
Med 1999;131:281303.**Like sulfonylureas, meglitinides are insulin
secretagogues that bind to the sulfonylurea receptor, a subunit of
the ATP-sensitive potassium channel (KATP) on the plasma membrane
of pancreatic beta-cells. This subunit regulates the activity of
the potassium channel and binds ATP and ADP, functioning as a
glucose sensor and trigger for insulin release. In addition,
binding at this site increases intracellular ATP and decreases ADP,
closing the channel. The resulting membrane depolarization causes
opening of the voltage-dependent calcium channels (VDCC), leading
to calcium influx and subsequent increases in intracellular calcium
and insulin release.1 Meglitinides bind to a site on the
sulfonylurea receptor that accepts benzamido compounds, a site that
is distinct from the site that binds classic sulfonylureas.2
Meglitinides have a short half-life and generally produce a faster
and briefer stimulus to insulin secretion than sulfonlylureas
because of their rapid absorption.1
Ref 1,p 1463, C1, 1, L1-12, C1, 4, L1-3Ref 2,p 114, Fig
11.1legend, L11-16,2, L1-8
Ref 1, p 1463,C1, 4, L1-3ReferencesBuse JB, Polonsky KS, Burant
CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams
Textbook of Endocrinology. 10th ed. Philadelphia: Saunders,
2003:14271483. Williams G, Pickup JC, eds. Handbook of Diabetes,
3rd ed. Malden, MA: Blackwell Publishing, 2004.
Ref 1,p 1463,C1, 1, L1-12, 4, L1-3Ref 2,p 114, Fig 11.1legend,
L11-16,2, L1-8
*Like sulfonylureas, meglitinides such as repaglinide and
nateglinide increase insulin release from the pancreas by
stimulating beta-cells, and as such depend on the presence of
functioning beta-cells to exert their efficacy.1,2 These drugs are
used to control postprandial hyperglycemia and are thus taken with
meals.1Dosed two, three, or four times daily,3,4 the meglitinides
are associated commonly with undesirable effects, such as weight
gain, but their main risk is related to hypoglycemia.5
Ref 1, p 114, 2, L1-8Ref 2, p 2614, C1, 2, L3-6Ref 1, p 114, 2,
L8-9
Ref 3, p 2, C4, 7, L1-4 Ref 4, p 11, 4, L1-2
Ref 5, p 298, C1, 1, L5-6Ref 1,p 114, 2, L1-8
Ref 2, p 2614, C1, 2, L3-6
Ref 3, p 2, C4, 7, L1-4 Ref 4, p 11, 4, L1-2
Ref 5, p 298, C1, 1, L5-6
ReferencesWilliams G, Pickup JC, eds. Handbook of Diabetes. 3rd
ed. Malden, MA: Blackwell Publishing, 2004. Riddle MC. Oral
pharmacologic management of type 2 diabetes. Am Fam Physician
1999;60(9):26132620.Prandin prescribing information, Novartis
Pharmaceuticals, December 2000.Starlix prescribing information,
Novartis Pharmaceuticals, December 2000.DeFronzo RA. Pharmacologic
therapy for type 2 diabetes mellitus. Ann Intern Med
1999;131:281303.*Metformin, the most widely used agent in the
biguanide class,1 exerts its antihyperglycemic effects via two
mechanisms that have not been fully elucidated at this time.2,3 The
primary action is to reduce hepatic glucose production.2,4
Metformin also reduces fatty acidinduced insulin resistance by
increasing insulin-stimulated glucose uptake in skeletal muscle and
adipocytes.2
Ref 1 p 291, C1, L2-4
Ref 2, p E-31, C1, 2, L1-4Ref 3, p 112, 1, L3-5 Ref 2, p E-31,
C1, 2, L1-4Ref 4, p 2065, C1, 1, L1-10;p 2068, C1, 2, L1-6,
11-13
Ref 2, p E-26, C2, 3, L1-5;p E-28, Fig 2 legend, L1
ReferencesDeFronzo RA. Pharmacologic therapy for type 2 diabetes
mellitus. Ann Intern Med 1999;131:281303.Kirpichnikov D, McFarlane
SI, Sowers JR. Metformin: An update. Ann Intern Med
2002;137(1):2533.Williams G, Pickup JC, eds. Handbook of Diabetes.
3rd ed. Malden, MA: Blackwell Publishing, 2004. Hundal RS, Krssak
M, Dufour S et al. Mechanism by which metformin reduces glucose
production in type 2 diabetes. Diabetes 2000;49(12):20632069. Ref
4, p 2065, C1, 1, L1-10;p 2068, C1, 2, L1-6, 11-13
Ref 2, p E-26, C2, 3, L1-5;p E-28, Fig 2 legend, L1Ref 2, p
E-31, C1, 2, L1-4
*Metformin exerts its antihyperglycemic effects by decreasing
hepatic glucose production and increasing peripheral glucose
uptake; its efficacy in improving peripheral insulin sensitivity
depends on the presence of insulin.1 In addition to decreasing
HbA1c levels, metformin reduces plasma triglyceride and LDL-C
levels.2 Metformin is administered once or twice daily with
meals.3The most common side effects are gastrointestinal (GI)
disturbances (nausea, anorexia, and diarrhea), which affect about
one-third of patients.4 Lactic acidosis is a rare but potentially
fatal side effect of metformin therapy.4 It may be avoided by not
giving metformin to patients with renal, hepatic, cardiac, or
respiratory failure and to those with a history of alcohol
abuse.3
Ref 1, p E-26, C2, 3, L1-5; p E-27, C1, 2, L1-2
Ref 2, p 293, C2, 2, L1-4
Ref 3, p 5,C1, 7, L1-2
Ref 4, p 112, 1, L9-11
Ref 4, p 112, 1, L9-11
Ref 3, p 3,Warnings box
ReferencesKirpichnikov D, McFarlane SI, Sowers JR. Metformin: An
update. Ann Intern Med 2002;137(1):2533.DeFronzo RA. Pharmacologic
therapy for type 2 diabetes mellitus. Ann Intern Med
1999;131:281303.Glucophage/Glucophage XR prescribing information,
Bristol-Myers Squibb, April 2003.Williams G, Pickup JC, eds.
Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing,
2004.Ref 1, p E-26, C2, 3, L1-5
Ref 1, p E-27, C1, 2, L1-2
Ref 3,p 5, C1, 7, L1-2
Ref 4, p 112, 1, L9-11
Ref 4, p 112, 1, L9-11
*Unlike other oral agents used in the treatment of type 2
diabetes, alpha-glucosidase inhibitors do not act by reversing any
of the pathophysiologic abnormalities of the diseaseincreased
hepatic glucose production, decreased muscle glucose uptake, or
impaired insulin release. Rather, alpha-glucosidase inhibitors
inhibit the terminal step of carbohydrate digestion at the brush
border of the intestinal epithelium. Carbohydrate absorption is
thus shifted to more distal parts of the intestine and colon and
thereby delayed. Alpha-glucosidase inhibitors do not cause
malabsorption, however. By slowing digestion/absorption, glucose
entry into the circulation is delayed. This allows the beta-cell
time to augment insulin release in response to an increase in
plasma glucose.1,2
Ref 1,p 282, Fig 1;p 294, C1, 2, L7-16Ref 2,p 1463, C2, 3,
L1-6ReferencesDeFronzo RA. Pharmacologic therapy for type 2
diabetes mellitus. Ann Intern Med 1999;131:281303.Buse JB, Polonsky
KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds.
Williams Textbook of Endocrinology. 10th ed. Philadelphia:
Saunders, 2003:14271483.Ref 1,p 282, Fig 1;p 294, C1, 2, L7-16
Ref 2,p 1463, C2, 3, L1-6
*Insulin sensitization achieved with PPAR-gamma agonists occurs
through several potential mechanisms. In adipose tissue, binding to
the PPAR-gamma receptor results in specific changes in adipose gene
expression. Altered expression of fatty acid transport genes may
contribute to reduced production of free fatty acids, which
improves insulin sensitization in muscle and in the liver.1By
modifying the expression of genes such as 11 beta-hydroxysteroid
dehydrogenase type 1, which converts cortisone to cortisol,
PPAR-gamma agonists may increase insulin action in adipocytes.
PPAR-gamma agonists may also have a role in reducing expression or
activity of insulin resistance factors such as TNF-alpha, resistin,
and adiponectin, thereby potentially increasing glucose utilization
and insulin action in liver and muscle.1
Ref 1, p 825, Fig 4 legend, L1-12
Ref 1, p 825, C2, 2,L14-16,Fig 4 legend, L12-16
Ref 1, p 825, Fig 4 legend,L16-21,C1, 1, L1
ReferenceMoller DE. New drug targets for type 2 diabetes and the
metabolic syndrome. Nature 2001;414:821828.Ref 1, p 825, Fig 4&
legend
*PPAR-gamma agonists act by enhancing insulin sensitivity in
liver and muscle tissues,1 and as such depend on the presence of
insulin in order to exert their therapeutic effects.2 Rosiglitazone
can be dosed once or twice daily; pioglitazone is dosed once
daily.3,4Side effects of PPARs include weight gain, edema, and
anemia;3,4 the main risk associated with these agents is that of
heart failure due to fluid retention.3,4Because of the potential
for weight gain and fluid retention, caution is recommended when
administering these agents with insulin or to patients with a
history of cardiac failure or renal insufficiency. The first PPAR,
troglitazone, was withdrawn from the market because of
hepatotoxicity; regular liver function tests are recommended for
patients taking rosiglitazone and pioglitazone.5
ReferencesMoller DE. New drug targets for type 2 diabetes and
the metabolic syndrome. Nature 2001;414:821828.Riddle MC. Oral
pharmacologic management of type 2 diabetes. Am Fam Physician
1999;60(9):26132620.Actos prescribing information, Takeda
Pharmaceuticals, December 2003.Avandia prescribing information,
GlaxoSmithKline, May 2004.Williams G, Pickup JC, eds. Handbook of
Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004. Ref 1, p
825, Fig 4 legend, L1-12
Ref 2, p 2615, C1, 4, L1-3, C2, 3, L1-2
Ref 3, p 2, C3, 9, L1Ref 4, p 21, 2, L1-3
Ref 3, p 2, C1, 17,18,20Ref 4, p 14, 2, L1-2;p 19, 5, L1-4
Ref 3, p 2, C1, 9, L1-3 Ref 4, p 12, 6, L1-3Ref 5, p 115, 2,
L1-10
Ref 1, p 825, Fig 4 legend, L1-12
Ref 2, p 2615, C1, 4, L1-3, C2, 3, L1-2
Ref 3, p 2, C3, 9, L1 Ref 4, p 21, 2, L1-3
Ref 3, p 2, C1, 17,18,20Ref 4, p 14, 2, L1-2;p 19, 5, L1-4
Ref 3, p 2, C1, 9, L1-3 Ref 4, p 12, 6, L1-3
Ref 5, p 115, 2, L1-10
***DISCUSSIONIn the peripheral tissues, the majority of the
effects of glucagon-like peptide 1 (GLP-1) are mediated by direct
interaction with the specific tissue GLP-1 receptorsIndirect
mechanisms of action of GLP-1 occur in liver, adipose, and muscle
tissues
BACKGROUNDGLP-1 is synthesised and released from the L-cells
located predominantly in the ileum and colon, and to a lesser
extent, in the duodenum and jejunumThere are multiple sites of
GLP-1 action, including pancreatic beta and alpha cells, and the
gastrointestinal, cardiovascular, and central nervous (CNS)
systemsActions are receptor mediatedThrough indirect actions, such
as inhibiting hepatic glucose production and stimulating glucose
uptake in fat and muscle, GLP-1 can influence glucoregulatory
physiological responses
*The various therapeutic agents available for the treatment of
type 2 diabetes act on different pathways to hyperglycemia.
Sulfonylureas act in the pancreas, stimulating insulin release by
binding to the sulfonylurea receptor of beta-cell membranes.1,2
Meglitinides, derived from the nonsulfonylurea benzamide portion of
glibenclamide, also act in the pancreas, stimulating insulin
release by binding to the benzamide site on beta-cells.1 They are
used to control postprandial hyperglycemia.PPARs (peroxisome
proliferator-activated receptor agonists, also known as glitazones
or thiazolidinediones) act primarily in muscle, but also exert
effects in the liver and adipose tissue. These agents reduce
insulin resistance by entering cells and bind to the nuclear
peroxisome proliferator-activated receptor-gamma (PPARg), leading
to enhanced expression of certain proteins involved in glucose and
lipid metabolism. This action increases glucose uptake, decreases
circulating fatty acids, and may also decrease the production of
mediators involved in the pathogenesis of insulin
resistance.1,2Alpha-glucosidase inhibitors lower postprandial blood
glucose concentrations by inhibiting disaccharidase enzymes in the
gut, thereby delaying carbohydrate absorption.1 This action retards
glucose entry into the systemic circulation, allowing beta-cells
ample time to increase insulin release.2 These agents require
adequate beta-cell function to be effective and may therefore be
more suitable for use early in the course of type 2
diabetes.Biguanides, of which metformin is the most widely used,
act primarily in the liver by decreasing hepatic glucose output
through a mechanism that has not been fully
elucidated.1,2Subcutaneous injection of insulin supplements
endogenous insulin production; in the basal state, insulin acts in
the liver to decrease glucose production, whereas in the
postprandial state, insulin facilitates glucose uptake into muscle
as well as fat.3
Ref 1, p 112, 2, L1-2Ref 2, p 288, C1, 2, L1-3
Ref 1, p 114, 2, L1-8Fig. 11.11 legend, L11-16
Ref 1, p 115, 1, L1-13Ref 2, p 282, Fig 1
Ref 1, p 116, 1, L1-5Ref 2, p 294, C1, 1, L1-3,C1, 2, L7-14
Ref 1, p 112, 1, L3-5 Ref 2, p 282, Fig 1;p 291, C1, L2
Ref 3,p 1463, C2, 4, L3; p 1464,C1, L1-6
Ref 1, p 112, 2, L1-2Ref 2, p 288, C1, 2, L1-3
Ref 1, p 114, 2, L1-8Fig. 11.11 legend, L11-16
Ref 1, p 115, 1, L1-13Ref 2, p 282, Fig 1
Ref 1, p 116, 1, L1-5Ref 2, p 294, C1, 1, L1-3, C1, 2, L7-14
Ref 1, p 112, 1, L3-5 Ref 2, p 282, Fig 1; p 291, C1, L2
Ref 3, p 1463, C2, 4, L3;p 1464, C1, L1-6References1.Williams G,
Pickup JC, eds. Handbook of Diabetes, 3rd ed. Malden, MA: Blackwell
Publishing, 2004.2.DeFronzo RA. Pharmacologic therapy for type 2
diabetes mellitus. Ann Intern Med 1999;131:281303.3.Buse JB,
Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et
al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia:
Saunders, 2003:14271483.*********
