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RECENT DEVELOPMENTS IN THE TREATMENT OF DIABETES MELLITUS.

INTRODUCTION:
DEFINITION:
Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia
resulting from defects in insulin secretion, insulin action, or both. The chronic
hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure
of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels.
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It is of two types: 1.diabetes mellitus type-1( DM-1)
2.diabetes mellitus type-2 . (DM-2) .
ETIOLGY:
DIABETES MELLITUS TYPE -1 :
This form of diabetes results from autoimmune destruction of the cells of the pancreas .
Markers of immune destruction of the cell are present at the time of diagnosis in 90% of
individuals and include islet cell antibodies ,antibodies to glutamic acid decarboxylase ,
and antibodies to insulin. While this form of diabetes usually occurs in children and
adolescents, it can occur at any age . Younger individuals typically have a rapid rate of
cell destruction and present with ketoacidosis , while adults often maintain sufficient
insulin secretion to prevent ketoacidosis for many years , which is often referred to as
latent autoimmune diabetes in adults .
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2. Certain drugs and chemicals may also play a role in the development of type-1
diabetes by destroying the pancreatic beta cells. These include chemicals such as
pyrinuron (Vacor, N-3-pyridylmethyl-N'-p-nitrophenyl urea) which is used as a rat
poison and is no longer used in the USA. An anticancer and antibiotic agent called
streptozotocin used to treat pancreatic cancer also destroys the pancreatic beta cells.
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DIABETES MELLITUS TYPE-2 :
The etiology of type 2 diabetes mellitus appears to involve complex interactions between
environmental and genetic factors.The disease develops when a diabetogenic lifestyle
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(ie, excessive caloric intake, inadequate caloric expenditure, obesity) is superimposed on
a susceptible genotype.
1.The body mass index (BMI) at which excess weight increases risk for diabetes varies
with different racial groups. For example, compared with persons of European ancestry,
persons of Asian ancestry are at increased risk for diabetes at lower levels of overweight.

2.Hypertension and prehypertension are associated with a greater risk of developing
diabetes in whites than in African Americans.
3.In addition, an in utero environment resulting in low birth weight may predispose
some individuals to develop type 2 diabetes mellitus.

4. Infant weight velocity has a small, indirect effect on adult insulin resistance, and this
is primarily mediated through its effect on BMI and waist circumference.
5.About 90% of patients who develop type 2 diabetes mellitus are obese.
6. However, a large, population-based, prospective study has shown that an energy-
dense diet may be a risk factor for the development of diabetes that is independent of
baseline obesity.
7.Some studies suggest that environmental pollutants may play a role in the
development and progression of type 2 diabetes mellitus.


8.Secondary diabetes may occur in patients taking glucocorticoids or when patients
have conditions that antagonize the actions of insulin (eg, Cushing syndrome,
acromegaly, pheochromocytoma).
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9. History of impaired fasting glucose or impaired fasting glucose tolerance.
10. Compromised function of the pancreatic -cell such that insulin secretion is
insufficient to match the degree of insulin resistance.
11. Elevated levels of triglycerides levels in muscle(intra myocellular lipids) also cause
insulin resistance. And these are considered most important cause nowadays i;e even
more important than BMI.
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PATHOPHYSIOLOGY:
PHYSIOLOGY: Mechanisms by which various classes of extracellular signals regulate
insulin secretion are discussed regarding their cellular and molecular actions. Under
physiological circumstances, the small postprandial changes in plasma glucose
concentrations (4.46.6 mM) primarily serve as a conditional modifier of insulin
secretion and dramatically alter the responsiveness of islets to a combination of
neurohumoral agonists. These agonists have two functions. Cholecystokinin (CCK) and
acetylcholine activate the hydrolysis of polyphosphoinositides, and gastric inhibitory
polypeptide (GIP) and glucagon like peptide 1 activate adenylate cyclase. These two
functional classes of neurohumoral agonists act synergistically to enhance insulin
secretion when plasma glucose is >6.0 mM but not when it is 4 mM. On the other
hand, an increase in plasma glucose concentration to 810 mM induces an increase in
insulin secretory rate in the absence of any of the neurohumoral agonists. Remarkably,
high glucose leads to an increase in the same intracellular signals, as does a combination
of acetylcholine and GIP. The regulation of insulin secretion occurs in three stages:
cephalic, early enteric, and later enteric. In this view, the crucial event occurring during
the first two phases is the agonist induced translocation of protein kinase C (PKC) to the
plasma membrane under conditions in which an increase in Ca
2+
influx does not occur.
PKC is now in a cellular location and a Ca
2+
-sensitive conformation such that an
increase in Ca
2+
influx rate occurring during the third phase leads to its immediate
activation and an enhanced rate of insulin secretion. Furthermore, under physiological
circumstances, an optimal insulin secretory response is dependent on a correct temporal
pattern of signals arising from neural and enteric sources. If this pattern is deranged, an
abnormal pattern of insulin secretion is observed. An important new insight is provided
by the observation that agonists (e.g., CCK or acetylcholine) that act to stimulate the
hydrolysis of phosphatidylinositides, when acting for a short period (1020 min),
induce an enhanced responsiveness of islets to glucose, i.e., proemial sensitization.
However, when acting unopposed for several hours, these agonists will induce a time-
dependent suppression of responsiveness to glucose and other agonists. Optimal insulin
secretion is dependent on periodic rather than continuous exposure to the correct
pattern of extracellular signals. The clinical implications of these new observations are
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discussed regarding glucose toxicity, the possible role of interleukin 1 in the
pathogenesis of insulin-dependent diabetes, sulfonylurea therapy, and the abnormalities
of insulin secretion seen in non-insulin-dependent diabetes.
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PATHOGENESIS:
Diabetes mellitus type -1 :
Diabetes mellitus type 1 is an autoimmune disease. The autoimmune process begins
many years before clinical detection and presentation. It is directly against beta cell of
the islets of Langerhans. The destruction must be very heavy, more than 90 percent of
beta cells must be destroyed for clinical symptoms to develop. The speed of the beta cell
destruction is variable. What is a trigger for autoimmune destruction is not known.
Autoantibody presence in serum are:
ICA (Islet cell antibodies) - against the antigen present in the cytoplasm of the endocrine
cells in pancreatic islets.
IAA (Insulin auto antibodies)
GAD auto antibodies to glutamic acid decarboxylas.
IA-2A (Insulinoma associated 2 auto antibodies) - against the protein tyrosine
phosphatase.
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Diabetes mellitus type-2 :
In type 2 diabetes the body either produces inadequate amounts of insulin to meet the
demands of the body or insulin resistance has developed. Insulin resistance refers to
when cells of the body such as the muscle, liver and fat cells fail to respond to insulin,
even when levels are high. In fat cells, triglycerides are instead broken down to produce
free fatty acids for energy; muscle cells are deprived of an energy source and liver cells
fail to build up glycogen stores. This also leads to an overall rise in the level of glucose in
the blood. Glycogen stores become markedly reduced and there is less glucose available
for release when it may be needed. Obesity and lack of physical activity are thought to be
major causes of insulin resistance.
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TREATMENT:
Diabetes type-1:
1. Early treatment of non obese diabetic (NOD) rats with CTLA4Ig prevents the
diabetes development. This development of autoimmune disease in the NOD
mouse begins at between 2 to 4 weeks of age due to infiltration of islets of
langerhans by lymphocytes. This insulitis leads to development of complete
diabetes at 8 to 10 weeks of age. So, the animals were injected with hCTLA4Ig
which interacts with anti B7 -2antibody which helps in preventing the disease.
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2. Recent introduction to the insulin market has been insulin glargine, which
functions as a very long acting insulin (peakless basal insulin). Combinations of
engineered very long acting insulins and rapid acting insulins can provide control
and convenience similar to that obtained with insulin pumps.
3. Islet transplantation with modified immunosuppressive regimens can cure type 1
diabetes. Islet transplantation is a consideration for the limited but important
subset of patients with recurrent severe hypoglycaemic episodes not responsive
to medical management. Inability to control autoimmunity and alloimmunity and
a lack of donor organs limit the application of islet transplantation.
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Treatment of diabetes type-2:
1.Dipeptidyl peptidase-4 inhibitors :
These protect a natural compound in the body glucagon like peptide-1(GLP-1) from
breaking down. GLP-1 helps lower blood glucose.
Drugs: 1.Januvia
2. Nesina.
3. Onglyza
4. Tradjenta.
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5.Alogliptin
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2.Incretin mimetics or GLP analogs: They use the bod. y's own signaling system to
boost insulin after meals.
Drugs : Injected drugs
1. Byetta
2. Victoza
3.Sodium-glucose co-transporter 2 (SGLT2) inhibitors:
They work by blocking glucose from being reabsorbed by the kidneys. That raises the
amount of glucose urinated, and lowers the amount of glucose in the blood. Currently,
Invokana (canaglifozin) is the only drug in this class that's approved by the FDA. More
SGLT2 inhibitors are being developed.
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4.Other drugs :
It helps lower blood sugar after meals in people with diabetes who use insulin.
Drugs: 1. Symilin, an injectable synthetic hormone.
5.Combination drugs:
They join different medications in one pill ; often metformin and a sulfonylurea, a
meglitinide, a DPP4 inhibitor, a thiazolidinedione, or a thiazolidinedione in combination
with a sulfonylurea. Combination drugs include Actoplus MET, Avandamet, Duetact,
Glucovance, Metaglip, Kazano, Oseni, and PrandiMet.
6.New types of insulin :
They allow some people to take just one injection of a long-acting insulin each day. That
can be much easier than multiple injections of standard insulin such asinsulin releasing
glucokinase.
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REFRENCE(S):
1. http://care.diabetesjournals.org/content/32/Supplement_1/S62.full
2. Pharmacotherapy: A Pathophysiologic Approach, 8e.Joseph T. DiPiro, Robert L.
Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey
3. http://emedicine.medscape.com/article/117853-overview#aw2aab6b2b3
4. http://diabetesdiabetesjournals.needdiets.com/cgi/content/full/51/1/7
5. http://care.diabetesjournals.org/content/13/6/655.abstract
6. http://www.news-medical.net/health/Diabetes-Mellitus-Type-1-
Pathophysiology.aspx
7. http://autoimmune.pathology.jhmi.edu/diseases.cfm?systemID=3&DiseaseID=23
8. http://www.news-medical.net/health/Diabetes-Mellitus-Type-2-
Pathophysiology.aspx
9.Pharmacotherapy: A Pathophysiologic Approach, 8e.Joseph T. DiPiro, Robert L.
Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey

10.www.jem.rupress.org
11. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC381328/
12. http://www.joslin.org/Aaron-Cypess-MD-PhD.html
13. http://www.webmd.com/diabetes/features
14. http://www.australianprescriber.com/magazine/37/1/28/35/new-
drugs/1043/canagliflozin-for-type-2-diabetes
15. http://www.australianprescriber.com/magazine/37/1/28/35/new-
drugs/1042/alogliptin-for-type-2-diabetes
16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464757/
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