Diabetes mellitus (DM) refers to a group
of common metabolic disorders that share the phenotype of hyperglycemia.
Several distinct types of DM exist and are caused by a complex interaction of
genetics and environmental factors. Depending on the etiology of the DM,
factors contributing to hyperglycemia include reduced insulin secretion,
decreased glucose utilization, and increased glucose production.(1)
Pathophysiology of type 2 diabetes
mellitus
Type 2 DM is characterized by impaired
insulin secretion, insulin resistance, excessive hepatic glucose production,
and abnormal fat metabolism. Obesity, particularly visceral or central (as
evidenced by the hip-waist ratio), is very common in type 2 DM (2)
The pathophysiology of type 2 diabetes
includes, impaired insulin secretion, impaired insulin action, insulin
resistance (3) and impaired incretin effect on β-cell function and
non-suppression of the action of α-cells, with rising blood glucose levels.
Most important biochemical perturbations
in type 2 diabetes mellitus involves peripheral and hepatic insulin resistance,
and impaired β-cell function. In type 2 diabetes, adipose tissue in general and
visceral fat in particular, exhibits a decreased inhibition of lipolysis and
increased lipoprotein lipase activity, both resulting in a heightened flux of
fatty acids in the liver and other tissues.
The skeletal muscle glucose utilization
is impaired to a greater degree than adipose tissue in type 2 diabetes (4).
This leads to impaired post-prandial glycogen deposition in muscles. The cause
of this resistance is a high free fatty (FFA) concentration in the myocytes.
The hepatic insulin resistance leads to
enhanced gluconeogenesis and glucogenolysis leading to increased hepatic
glucose production, a hallmark of uncontrolled diabetes.
In type 2 diabetics, rapid meal-related
insulin secretion (approx. 30 mins post-meal) is attenuated. Also, there is
impaired rapid oscillation of insulin without any glycemic stimulus. The β-cell
mass appears to be slightly reduced at the time of diagnosis. However, the
functional capacity is impaired out of proportion to its mass.
Other pathogenetic mechanism involves
incretins – a group of hormones secreted by gastrointestinal tract. Two
extremely well known members glucagon like peptide (GLP-1) and glucose
dependent insulinotropic peptide (GIP). The former is secreted from L cells of
ileum and latter from the K cells located in the proximal small intestine.
These hormones account for the enhanced insulin secretory response upon
ingestion of glucose orally, as compared to that obtained by intravenous
glucose administration. This has been termed the incretin effect (5). In the
type 2 diabetes, the incretin effect is blunted, which can be corrected by
injecting GLP-1 or its longer acting analogue, like exenatide or liraglutide.
GLP-1 is normally destroyed by a group of enzymes called dipeptyl peptidases,
of which dipeptyl peptidase-IV (DPP-IV) is the predominant one. Compounds
inhibiting DPP-IV inhibitors prolong the effect of endogenous GLP-1 and are
being used therapeutically at present.
Thiazolidinediones regulate
transcription of genes involved in lipid and glucose metabolism, and is
expressed in all insulin sensitive tissues even in pancreatic beta cells but
mainly in adipocytes. TZDs stimulates PPAR-gamma
agonists, increases number of small, insulin sensitive adipocytes which
enhances glucose uptake, improves glycemic status, improve insulin
sensitivities and protect beta cells by lowering the demand on, glucotoxicity
and lipotoxicity(6)
Sulphonylureas bind to a specific site
on the β
cell KATP channel complex (the sulfonylurea receptor, SUR) and
inhibit its activity.
Anti-diabetic drugs to be used
1) Agents
stimulating insulin release (secretagogues)
(A)
Suphonylureas
Glibenclamide, Glipizide, Gliclazide and Glimepirid
(B)
DPP-IV inhibitors
Sitagliptin, Vildagliptin and Saxagliptin
2) Agents
lowering insulin resistance (sensitisers)
(A)
Biguanides: Metformin
(B)
Thiazolidinediones:
Pioglitazone and Rosiglitazone |