New treatment for Diabetes Mellitus and Drugs to treat Hypoglycemia

New Treatment For Diabetes Mellitus
Drugs To Treat Hypoglycemia
Faraza Javed
Mphil Pharmacology

guidelines.diabetes.ca | 1-800-BANTING (226-8464) | diabetes.ca
Copyright © 2013 Canadian Diabetes Association
Diabetes Mellitus
Diabetes mellitus is a
group of metabolic
diseases characterized
by hyperglycemia
resulting from defects
in insulin secretion,
insulin action, or both.

Treatment
 Synthetic Amylin Analog
 Incretin Mimetics
 Oral Agents
Insulin Sectretagogues
Alpha Glucosidase Inhibitors
Dipeptidyl Peptidase IV Inhibitors
Insulin Sensitizers

Synthetic Amylin Analog
• Pramlintide, a synthetic analogue of amylin, is an
injectible antihyperglycemic agents that modulates
postprandial glucose levels and is approved for
postprandial use for persons with type 1 and type 2
diabetes.
• Pramlintide lowers glucagon during a meal, slows
food emptying from the stomach and curbs the
appetite.

• It is administered in addition to insulin who are
unable to achieve their target postprandial blood
sugar level.
• Major adverse effects are hypoglycemia and GI
symptoms including nausea, vomiting and anorexia.

Glucagon like Polypeptide- 1
Receptors Agonists
• Incretins are intestinal factors that are released in
response to nutrients, contributing to blood glucose
lowering.
• In type 2 Diabetes, the release of glucagon like
polypepide is diminished postprandially, which leads
to inadequate glucagon suppression and excessive
hepatic glucose output.

• Two synthetic analogues of glucagon likepolypeptide
Exenatide and Liraglutide are commercially
available to help restore GLP-1 activity.
• Exenatide and Liraglutide, along with DPP-4
inhibitors, are currently available to treat patients
with T2DM by addressing decreased concentrations
of GLP-1.

Insulin Pump
Insulin pumps are small computerized devices that
deliver insulin in two ways:
• In a steady measured and continuous dose (the "basal" insulin)
• As a surge ("bolus") dose, at your direction, around mealtime.
This FDA Approved Insulin delivery system most closely mimics
the body's normal release of insulin.

Combination Therapy
• GLP-1 (Glucagon like Polypeptide) Receptor agonist
with Insulin Secretagogue or with Insulin.
• DPP-4 (Dipeptidyl Peptidase IV) Inhibitor Sitagliptin
or Vidagliptin (Glavusmet) in combination with
metformin.
• Pramlintide in combination with Insulin, Metformin
or Sulphonylurea.

Modern Advancement in DM
Treatment
The current classes of medications are effective initially,
but glucose-lowering effects are not typically
sustained long term as beta cell dysfunction
progresses. Several new classes of medications are
currently in development, as well as a new long-
acting insulin.

There are two organizations that are reviewing the DM
therapy treatment and encouraging new reasearches:
• American Diabetes Association (ADA)
• International Diabetes Federation (IDF)

Sodium Glucose Cotransporter 2
Inhibitors (SGLT-2)
SGLT-2, a low-affinity but high-capacity transporter
found in the brush border of the proximal tubule, is a
mediator of glucose reabsorption in the kidneys. In
hyperglycemia, the kidneys may play an exacerbating
role by reabsorbing excess glucose, ultimately
contributing to chronic hyperglycemia, which in turn
contributes to chronic glycemic burden and the risk of
microvascular consequences.

• SGLT-2 inhibitors exert their effects by causing the
kidneys to excrete glucose into the urine. The effects
are also independent of insulin secretion.
• These proposed mechanisms make SGLT-2 a viable
target to help combat hyperglycemia in patients with
T2DM. These agents decreased A1C anywhere from
0.5 to 1.5%, and demonstrated low incidences of
hypoglycemia with minimal side effects.

SGLT-2 Inhibitors (Phase III) include:
• Canagliflozin
• Empagliflozin
• Dapagliflozin

Long Acting Basal Insulin Analogue
LY2605541 is a long-acting basal insulin analogue that
is currently being evaluated in phase III studies in
T2DM patients. The primary aim of insulin therapy is
to replace endogenous insulin secretion in patients
with type 1 or type 2 diabetes in a physiologic
manner, mimicking normal secretion patterns to
adequately regulate glucose metabolism.

• The currently available human insulins for basal
therapy - neutral protamine Hagedorn (NPH), - and
analogs such as insulin glargine, differ in
pharmacokinetic properties.
• Clinical trial data indicate that insulin glargine may
satisfy basal insulin requirements, with an improved
safety profile relative to other available insulins used
for basal supplementation.

11-β-Hydroxysteroid Dehydrogenase
Type 1 Inhibitors (11-β-HSD1)
11-β-Hydroxysteroid Dehydrogenase or cortison
reductase convert cortison to cortisol.
Overexpression of this enzyme can lead to obesity
insulin resistance.

Preclinical evidence indicates that 11-β-HSD1 has a
function in both obesity and metabolic disease in
rodents, which suggests that inhibiting this catalyst in
liver and adipose tissues may lead to enhanced
hepatic and peripheral insulin sensitivity, thus
improving overall glucose levels and possibly
decreasing overall macrovascular risk.

Vitamin D In DM
Recent studies have found that deficiency of Vitamin
D results in reduction in insulin secretion and thus
in hyperglycemia. Both insulin secretion and
sensitivity depends upon intracellular
calcium concentration also and Vitamin D is one of
the hormone which has been found to regulate
calcium flux within the cells. In both observational
and case-control studies, an inverse relationship has
been reported with level of 25(OH)Vit D and degree
of glycemic control.

Stem Cell Therapy
A newly created method of
placing stem cell-derived
pancreatic cells in capsules
under the skin to replace
insulin is tested in diabetic
disease models. The method is successful without
producing likely complications. The study confirms
the viability of combining stem cells and
'encapsulation' technology to treat insulin-dependent
diabetes.

Betatrophin
Scientists at Harvard Stem Cell Institute (HSCI) found
that a hormone called betatrophin plays a significant
role in enhancing the production of insulin by beta
cells in mice.
If the study also shows similar results in humans, it will
be a huge leap forward in the treatment of diabetes.

Islet Cell Transplantation
In islet cell
transplantation,
beta cells are
removed from
a donor's pancreas
and transferred
into a person
with diabetes.

• Beta cells are found in the islets of the pancreas and
produce insulin, which regulates blood sugar levels.
Once transplanted, the donor islets begin to make and
release insulin.
• As with all organ and tissue transplants, rejection of
the donor cells is the greatest challenge.

Brown Fat Transplant May Aid in
Diabetes Management
There are at least two types of adipose (fat) tissue.
• White adipose tissue is the more common type that
lies below the skin, stores excess fat in the body, and
expands with weight gain.
• Brown adipose tissue, on the other hand, is derived
from muscle and is highly thermogenic. In other
words, it burns energy to produce heat and maintain
body temperature in warm-blooded organisms.

• Unlike white adipose tissue, the quantity of brown fat
in the body is inversely proportional to body mass
index (BMI), meaning that lean people tend to store
more of this type of fat than people that are
overweight , leading to the characterization of brown
fat as “good” fat.

• Researchers find out that brown fat transplant had
significantly lower body weight, reduced white fat
mass, show better sensitivity to insulin, and
improved glucose metabolism in labourtary animals.
• Now researchers are trying to collect data on humans
to evaluate either the study also shows similar results
in humans or not.

The Use of Vanadium Complexes
in Diabetes Mellitus
Recent researches found that vanadyl ion and its
complexes are effective not only in treating or
relieving both types of DM but also in preventing
the onset of DM. Exact mechanism is still
unknown.

Gastric Stimulator
DIAMOND, made by
the Israeli medical
device company
MetaCure, is an
implantable gastric
stimulator with
electrodes attached to the
outer stomach muscles.

• Its original purpose was to treat obesity But its
developers discovered that in the hundreds of people
implanted with DIAMOND worldwide, the device
also effectively controls blood glucose levels as well
as, or better than, synthetic insulin and other diabetes
medications. It also helped improve diabetes-
associated conditions such as high blood pressure,
cholesterol and triglycerides.

The Dead Sea
The mineral-rich Dead Sea
has long been known
as a natural treatment
for skin, rheumatic and
respiratory diseases.
According to a study by health sciences researchers
at Ben-Gurion University, the salty water also help
lower blood glucose levels and could improve the
medical conditions of diabetics.

• After soaking in a pool filled with Dead Sea water for
20 minutes, there was a considerable decrease – up to
13 percent in some cases – in the blood glucose
levels.
• It’s still a bit early to draw conclusions, but further
testing will determine if one day a Dead Sea dunk
could be prescribed as a way to lessen the dose of
insulin needed.

Hypoglycemia
Hypoglycemia is a condition characterized by
abnormally low blood glucose (blood sugar)
levels, usually less than 70 mg/dl.
• Hypoglycemia is not a disease itself – it is the
result of an underlying issue or combination of
them.

Causes
• Drugs e.g. Insulin, Sulphonylurea
• Endocrinopathies (Glucagon Deficiency)
• Tumor of B cells
• Poisoning (ethanol inhibits gluconeogenesis)
• Renal Failure

Mild Symptoms
• Trembling/shakiness
• Sweating
• Anxiety
• Irritability
• Pallor
• Palpitations
• Headache

Severe Symptoms
• Concentration problems
• Confusion
• Irrational and disorderly behavior
• Seizures
• Loss of consciousness

Treatment Protocol
Initially
• Glucose 10-20 g is given by mouth, either in liquid
form or as granulated sugar (2 teaspoons) or sugar
lumps.
• GlucoGel® - formerly known as Hypostop® Gel -
may be used.
• Repeat capillary blood glucose after 10-15 minutes; if
the patient is still hypoglycaemic then the above can
be repeated (probably up to 1-3 times).

Recommendation 1
1. Mild to moderate hypoglycemia should be
treated by oral ingestion of 15 g carbohydrate;
glucose or sucrose crystals/ solutions are
preferable to orange juice and glucose gels.
Patients should retest blood sugar in 15 minutes
and retreat with another 15 g of carbohydrates if
BG remains <70mg/dl

Recommendation 2
2. Severe hypoglycemia in a conscious person
should be treated by oral ingestion of 20 g of
carbohydrate, preferable as glucose tablets or
equivalent.
Blood sugar should be retested in 15 minutes,
and then retreated with a further 15 g of glucose
if BG remains <70 mg/dl.

Recommendation 3
3. Severe hypoglycemia in an unconscious individual:
– No IV access: 1 mg of glucagon should be
administered subcutaneously or intramuscularly.
– Hypoglycemic effects (specially due to drugs) may
persist for 12-24 hours and ongoing glucose
infusion or other therapies such as octreotide may
be required.

• With IV access: 10-25 g (20-50 cc of D50W) of
glucose should be given intravenously over 1-3
minutes.
• Retest in 15 minutes to ensure the BG >70mg/dl and
retreat with a further 15 g of carbohydrate if needed.
• Once conscious, eat usual snack or meal due at that
time of day or a snack with 15 g carbohydrate plus
protein.

Recommendation 4
Prolonged Hypoglycemic Coma:
Use IV mannitol and dexamethasone with constant
glucose monitoring and IV glucose to keep serum
level at 70-80mg/dl until either consciousness has
been restored or permanent brain damage is
diagnosed.

3. Once the patient is more alert, carbohydrate
should be given, e.g. toast, or a normal meal. For
inpatients, an infusion of 10% glucose may be
administered if required.

Recommendation 5
• Patients receiving antihyperglycemic agents that
may cause hypoglycemia should be counseled
about strategies for prevention, recognition and
treatment of hypoglycemia.

References
Katzung Pharmacology, 11th Edition
www.idf.org
SGC2I in DM Treatmet, Jcem. (2010) vol.95(1)
NIDDK, NIH Review (2014)
www.diabetes.org.uk
CDA clinical practice guidelines
ND Cohen, JE Shaw - Internal medicine journal, 2007.
C Kelly, NH McClenaghan - Stem cells international, 2011.
www.guidelines.diabetes.ca
Alexander, G Caleb. (2008). Trends in DM treatment. Archives
of internal medicine. 168(19):2088-2094.

New treatment for Diabetes Mellitus and Drugs to treat Hypoglycemia

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