28 May, 2010

Type 1 - Recent advances (Otelixizumab) !!

Otelixizumab, also known as TRX4, is a novel monoclonal antibody, which is being developed for the treatment of type 1 diabetes and other autoimmune diseases. The antibody is being developed by Tolerx, Inc. in collaboration with GlaxoSmithKline and is being manufactured by Abbott Laboratories.

As a monoclonal antibody, otelixizumab consists of two heavy chains and two light chains. The heavy chains are humanized γ1 (gamma-1) chains from rats, making otelixizumab an immunoglobulin G1. The light chains are chimeric human/rat λ (lambda) chains.

Mechanism of action

Otelixizumab is one of several investigational monoclonal antibodies that target CD3, a T lymphocyte receptor involved in normal cell signaling. More specifically, otelixizumab targets the epsilon chain of CD3. Data suggest that the drug works by blocking the function of effector T cells, which mistakenly attack and destroy insulin-producing beta cells while stimulating regulatory T cells, which are understood to protect against effector T cell damage, thus preserving the beta cells' normal ability to make insulin.

Clinical progress

The efficacy and safety of otelixizumab for the treatment of autoimmune type 1 diabetes is currently being studied in a pivotal Phase 3 study called DEFEND (Durable-response therapy Evaluation For Early or New-onset type 1 Diabetes). DEFEND is a randomized, placebo-controlled Phase 3 trial designed to enroll approximately 240 adult patients, age 18 to 35, with newly diagnosed autoimmune type 1 diabetes. DEFEND is being conducted at multiple centers in North America and Europe. The trial is designed to evaluate whether a single course of otelixizumab, administered not more than 90 days after the initial diagnosis, will reduce the amount of administered insulin required to control blood glucose levels by inhibiting the destruction of beta cells.

Orphan drug status

Otelixizumab has been granted Orphan Drug Status by the U.S. Food and Drug Administration.

Now whats orphan drug status???

An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease. The assignment of orphan status to a disease and to any drugs developed to treat it is a matter of public policy in many countries, and has resulted in medical breakthroughs that may not have otherwise been achieved due to the economics of drug research and development.

26 May, 2010


Liraglutide marketed under the brand name Victoza, is a long-acting glucagon-like peptide-1 (GLP-1) analog that has been developed by Novo Nordisk for the treatment of type 2 diabetes. The product was approved by the European Medicines Agency (EMEA) on July 3, 2009, and by the U.S. Food and Drug Administration (FDA) on January 25, 2010.

Liraglutide is marketed under the brandname Victoza in the U.S. and Europe. It has been launched in Germany, Denmark, the Netherlands, the United Kingdom, Ireland, and the United States.

Cancer concerns

On April 2, 2009, an FDA advisory panel reviewed the significance of malignant C-cell carcinoma and thyroid C-cell focal hyperplasia in rats and mice. Some say the tumors were caused by a non-genotoxic, specific receptor-mediated mechanism to which rodents are particularly sensitive whereas non-human primates and humans are not. The Victoza label carries a Black Box Warning, "Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza only to patients for whom the potential benefits are considered to outweigh the potential risk". The FDA said that serum calcitonin, a biomarker of medulliary thyroid cancer, was slightly increased in liraglutide patients but still within normal ranges, and it required ongoing monitoring for 15 years in a cancer registry.


Studies to date suggest liraglutide improves control of blood glucose. It reduces meal-related hyperglycemia (for 12 hours after administration) by increasing insulin secretion, delaying gastric emptying, and suppressing prandial glucagon secretion.

Liraglutide may have advantages over current therapies:

It acts in a glucose-dependent manner, meaning that it will stimulate insulin secretion only when blood glucose levels are higher than normal. Consequently, it shows negligible risk of hypoglycemia.
It has the potential for inhibiting apoptosis and stimulating regeneration of beta cells (seen in animal studies).
It decreases appetite and maintains body weight, as shown in a head-to-head study versus glimepiride.
It lowers blood triglyceride levels.
It has only mild and transient side effects, mainly gastrointestinal.


Liraglutide is a once-daily GLP-1 derivative for the treatment of type 2 diabetes. GLP-1, in its natural form, is short-lived in the body (the half-life after subcutaneous injection is approximately one hour), so it is not very useful as a therapeutic agent. However, liraglutide has a half-life after subcutaneous injection of 11–15 hours, making it suitable for once-daily dosing
The prolonged action of liraglutide is achieved by attaching a fatty acid molecule at one position of the GLP-1 molecule, enabling it to bind to albumin within the subcutaneous tissue and bloodstream. The active GLP-1 is then released from albumin at a slow, consistent rate. Binding with albumin also results in slower degradation and reduced elimination of liraglutide from the circulation by the kidneys compared to GLP-1

20 May, 2010

Insulin - Tissue clumps to Humulin!!

In 1869 Paul Langerhans, a medical student in Berlin, was studying the structure of the pancreas under a microscope when he identified some previously un-noticed tissue clumps(Islets of Langerhans) scattered throughout the bulk of the pancreas.

Edouard Laguesse later suggested that they might produce secretions that play a regulatory role in digestion. Paul Langerhans' son, Archibald, also helped to understand this regulatory role. The term insulin origins from Insel, the German word for islet/island.

In 1889, the Polish-German physician Oscar Minkowski in collaboration with Joseph von Mering removed the pancreas from a healthy dog to test its assumed role in digestion. Several days after the dog's pancreas was removed, Minkowski's animal keeper noticed a swarm of flies feeding on the dog's urine. On testing the urine they found that there was sugar in the dog's urine, establishing for the first time a relationship between the pancreas and diabetes.

In 1901, another major step was taken by Eugene Opie, when he clearly established the link - Diabetes mellitus … is caused by destruction of the islets of Langerhans and occurs only when these bodies are in part or wholly destroyed. Before his work, the link between the pancreas and diabetes was clear, but not the specific role of the islets.

In 1906 George Ludwig Zuelzer was partially successful treating dogs with pancreatic extract but was unable to continue his work.

Between 1911 and 1912, E.L. Scott at the University of Chicago used aqueous pancreatic extracts and noted a slight diminution of glycosuria but was unable to convince his director of his work's value; it was shut down.

Israel Kleiner demonstrated similar effects at Rockefeller University in 1919, but his work was interrupted by World War I and he did not return to it.

Nicolae Paulescu, a professor of physiology at the University of Medicine and Pharmacy in Bucharest, was the first one to isolate insulin, which he called at that time pancrein,

In October 1920 Canadian Frederick Banting was reading one of Minkowski's papers and concluded that it is the very digestive secretions that Minkowski had originally studied that were breaking down the islet secretion(s), thereby making it impossible to extract successfully. He decided to Ligate pancreatic ducts of the do, Keep dogs alive till acini degenerate leaving islets and try to isolate internal secretion of these and relieve glycosuria.

Banting's method was to tie a ligature (string) around the pancreatic duct, and when examined several weeks later, the pancreatic digestive cells had died and been absorbed by the immune system, leaving thousands of islets. They then isolated an extract from these islets, producing what they called isletin ( now know as insulin), and tested this extract on the dogs. Banting and Best were then able to keep a pancreatectomized dog named Alpha alive for the rest of the summer by injecting her with the crude extract they had prepared. Removal of the pancreas in test animals essentially mimics diabetes, leading to elevated blood glucose levels. Alpha was able to remain alive because the extracts, containing isletin, were able to lower her blood glucose levels.

In December 1921, Macleod invited the biochemist James Collip to help with this task and within a month the team felt ready for a clinical test.

On January 11, 1922, Leonard Thompson, a 14-year-old diabetic who lay dying at the Toronto General Hospital, was given the first injection of insulin. However, the extract was so impure that Thompson suffered a severe allergic reaction, and further injections were canceled.

Over the next 12 days, Collip worked day and night to improve the ox-pancreas extract, and a second dose was injected on January 23. This was completely successful, not only in having no obvious side-effects but also in completely eliminating the glycosuria sign of diabetes.

In one of medicine's more dramatic moments Banting, Best and Collip went from bed to bed injecting an entire ward with the new purified extract. Before they had reached the last dying child the first few were awakening from their coma to the joyous exclamations of their families.

Over the spring of 1922, Best managed to improve his techniques to the point where large quantities of insulin could be extracted on demand but the preparation remained impure.

The drug firm Eli Lilly and Company had offered assistance not long after the first publications in 1921 and they took Lilly up on the offer in April. In November Lilly made a major breakthrough and were able to produce large quantities of highly refined, 'pure' insulin. Insulin was offered for sale shortly thereafter.

The amino-acid structure of insulin was characterized in the 1950s and the first synthetic insulin was produced simultaneously in the labs of Panayotis Katsoyannis at the University of Pittsburgh and Helmut Zahn at RWTH Aachen University in the early 1960s.

The first genetically-engineered, synthetic "human" insulin was produced in a laboratory in 1977 by Herbert Boyer using E. coli. Partnering with Genentech founded by Boyer, Eli Lilly went on in 1982 to sell the first commercially available biosynthetic human insulin under the brand name Humulin.

16 May, 2010

Metformin - Corner stone of Type2 Diabetes

The main use for Metformin is in the treatment of Type2 Diabetes, especially in overweight people. Metformin is absorbed from the Small Intestine. Half life of Metformin is around 4-6hours. Oral bioavailablity is around 50-60%. Metformin is excreted unchanged via kidneys

Advantages of Metformin

.For Blood Sugar Control
.HbA1c reduction expected with metformin is approximately 1-2%
.Weight Loss ( Due to its insulin sparing effect)
.Increases Body's sensitivity to insulin ( decreases insulin resistance)
.Useful in females with Polycystic ovaries
.Facilitates normal mensturation and successful pregnancy
.Reduces Triglyceride and Free Fatty Acids level

Dose of Metformin ranges from 250mg - 3000mg/day

Side Effects of Metformin

-Lactic Acidosis ( Rare )

When to Avoid Metformin

.Renal Failure
.Hepatic Failure
.Cardiac Failure
.Respiratory Failure
.Alcohol Abuse
.During Contrast Radiological Procedures

History of the wonder drug - Metformin !!

Metformin belongs to Biguanide class of anti-diabetic drugs, which also includes the withdrawn agents Phenformin and Buformin, originates from the French lilac (Galega officinalis), a plant used in folk medicine for several centuries.

Metformin was first described in the scientific literature in 1922, by Emil Werner and James Bell

In 1929, Slotta and Tschesche discovered its sugar-lowering action in rabbits, noting that it was the most potent of the biguanide analogs they studied.

In 1950, metformin Eusebio Y. Garcia, used metformin (he named it Fluamine) to treat influenza; he noted that the drug "lowered the blood sugar to minimum physiological limit" in treated patients and was non-toxic. Garcia also believed metformin to have bacteriostatic, antiviral, antimalarial, antipyretic and analgesic actions but none of these effects were confirmed.

French diabetologist Jean Sterne studied the antihyperglycemic properties of galegine, an alkaloid isolated from Galega officinalis, which is structurally related to metformin

Later, working at Laboratories Aron in Paris, he was prompted by Garcia's report to re-investigate the blood sugar lowering activity of metformin and several biguanide analogs. Sterne was the first to try metformin on humans for the treatment of diabetes; he coined the name "Glucophage" (glucose eater)

Metformin became available in the British National Formulary in 1958. It was sold in the UK by a small Aron subsidiary called Rona.

Broad interest in metformin came after the withdrawal of the other biguanides in the 1970s. Metformin was approved in Canada in 1972, but did not receive approval by the U.S. Food and Drug Administration (FDA) for Type 2 diabetes until 1994. Produced under license by Bristol-Myers Squibb, Glucophage was the first branded formulation of metformin to be marketed in the United States, beginning on March 3, 1995. Generic formulations are now available in several countries, and metformin is believed to have become the most widely prescribed anti-diabetic drug in the world

10 May, 2010

Sexual Dysfunction in Diabetes

Sexual function is a complex blend of Anatomic, Neurological, Metabolic, Endocrine & Psychic factors. On an average around 50% male diabetics develop sexual dysfunction

What is essential for normal sexual function?

.Adequate desire & arousal
.Adequate testosterone levels
.Anatomically Normal Penis
.Adequate Arterial blood flow
.Effective Venous Occlusion ( To sustain Erection)
.Intact Nerve Supply

What leads to Sexual Dysfunction in Diabetics?
.Uncontrolled or fluctuating blood sugars
.Diabetic Neuropathy ( As a result of uncontrolled DM or long duration of DM)
.Endothelial Dysfunction
.Testosterone deficiency
.Uncontrolled Hypertension
.Iatrogenic ( Drug induced )

1)Transient or temporary dysfunction ( Due to blood sugar fluctuation)
2)Progressive Dysfunction ( Diabetic Erectile Failure)

1)Psychological counseling



3)Vasoactive agents

-Papaverin injection

4)Vaccum Constriction Devices ( VCD )


Vascular bypass ( Iliac-Pudendal, Pudendal-Cavernous, Pudendal-Penile grafts)
Semi rigid or Inflatable penile prosthesis implantation

09 May, 2010

Glucose Tolerance Test.

What is the glucose tolerance test?

The oral glucose tolerance test (OGTT) is the gold standard for making the diagnosis of type 2 diabetes. With an oral glucose tolerance test, the person fasts overnight (at least 8 but not more than 16 hours). Then first, the fasting plasma glucose is tested. After this test, the person receives 75 grams of glucose Blood samples are taken in 1st hour and 2nd hour.

Prerequisites for GTT

The person should be normally active and should not be taking medicines that could affect the blood glucose. For three days before the test, the person should have eaten a diet high in carbohydrates (150- 200 grams per day). The morning of the test, the person should not smoke or drink coffee/tea.

The classic oral glucose tolerance test measures blood glucose levels three times over a period of 2 hours. In a person without diabetes, the glucose levels rise and then fall quickly. In someone with diabetes, glucose levels rise higher than normal and fail to come back down as fast.

Glucose tolerance test- inference

Normal response: Fasting value < 100 mg/dl and 2nd hour value < 200 mg/dl

Impaired glucose tolerance: fasting glucose is less than 126 mg/dl and the 2-hour glucose level is between 140 and 199 mg/dl.

Diabetes: Fasting glucose is noted as greater than 126 mg/dl and 2nd hour sample more than 200mg/dl

07 May, 2010

Footwear for Diabetics

A very common problem encountered by atleast 30% of diabetics in India is foot ulcers. Ulcers occur mostly at high pressure points due to undue bony prominences or ill fitting footwear. So the first step to prevent a foot ulcer is to select proper footwear.

Criteria for selection of footwear

1)Select footwear made of MCP/MCR
2)Footwear should be light in weight ( Less than 700gms/pair)
3)Soles of foot wear must be Rigid ( To avoid any penetrating injury while walking)
4)Soles should have serrated edges ( To avoid slipping)
5)Heel height should not be more than 5cm
6)Length of the shoe should allow 1/2inch gap between the end of shoe and and longest toe
7)should have a strong heel counter
8)Footwear should have velcro/laces for adjustment in cases of edema ( swelling)
9)There should be extra depth to accommodate deformities and removable insoles
10)Should have high rounded toe box
11)Inner lining of the shoe should be soft to prevent friction injuries
12)Insoles should be soft to allow redistribution of pressure

06 May, 2010

Symptoms of Hypoglycemia & Hyperglycemia


jerky movements
sudden Hunger
Difficulty in speaking
Attention Deficit
Tingling sensations around the mouth
Feeling anxious or weak


Polyphagia - frequent hunger
Polydipsia - frequent thirst
Polyuria - frequent urination
Blurred vision
Fatigue (sleepiness).
Weight loss
Poor wound healing
Dry mouth
Dry or itchy skin
Tingling in feet or heels
Impotence (male)
Recurrent infections
hyperventilation: deep, rapid breathing

05 May, 2010

Type 2 Diabetes - High Risk Population

Obese people ( BMI more than 25 )
Age > 45 years
People with sedentary lifestyle
people with family history of diabetes ( First degree relatives with diabetes)
Women who have delivered Big Babies ( > 4.5kg birth weight )
Abnormal Lipid Profile ( Cholesterol HDL<35mg/dl & Triglycerides >150mg/dl )
Women diagnosed with Polycystic Ovaries
Glucose Tolerance Test indicating Prediabetes

Metabolic Syndrome - The Deadly Quarlet !!

Metabolic syndrome is a combination of disorders which increases the chances of developing Diabetes ( Type 2 )

Obesity ( Central Obesity )
Triglycerides > 150mg/dl
HDL < 35mg/dl ( Good Cholesterol)
Fasting Blood Sugar > 100mg/dl
Blood Pressure > 130/85mm of Hg

04 May, 2010

History Of Diabetes

The term diabetes was coined by Aretaeus of Cappadocia.
Thomas Willis added the word mellitus, from the Latin meaning "honey"

In 1776, Matthew Dobson confirmed that the sweet taste was because of an excess of a kind of sugar in the urine and blood of people with diabetes.

Diabetes mellitus appears to have been a death sentence in the ancient era.
Sushruta (6th century BCE) identified diabetes and classified it as Madhumeha. He further identified it with obesity and sedentary lifestyle,
The ancient Indians tested for diabetes by observing whether ants were attracted to a person's urine, and called the ailment "sweet urine disease" (Madhumeha).
Avicenna (980–1037) provided a detailed account on diabetes mellitus in The Canon of Medicine, "describing the abnormal appetite and the collapse of sexual functions," and he documented the sweet taste of diabetic urine.
He also described diabetic gangrene, and treated diabetes using a mixture of lupine, trigonella (fenugreek), and zedoary seed, which produces a considerable reduction in the excretion of sugar, a treatment which is still prescribed in modern times. Avicenna also "described diabetes insipidus very precisely for the first time",
Johann Peter Frank (1745–1821) who first differentiated between diabetes mellitus and diabetes insipidus.

The discovery of a role for the pancreas in diabetes is generally ascribed to Joseph von Mering and Oskar Minkowski, who in 1889 found that dogs whose pancreas was removed developed all the signs and symptoms of diabetes and died shortly afterwards.

In 1910, Sir Edward Albert Sharpey-Schafer suggested that people with diabetes were deficient in a single chemical that was normally produced by the pancreas—he proposed calling this substance insulin, from the Latin insula, meaning island, in reference to the insulin-producing islets of Langerhans in the pancreas.

The endocrine role of the pancreas in metabolism, and the existence of insulin, was further clarified in 1921, by Sir Frederick Grant Banting and Charles Herbert Best Banting, Best, and colleagues (especially the chemist Collip) went on to purify the hormone insulin from bovine pancreases.

Banting is honored by World Diabetes Day which is held on his birthday, November 14.

The distinction between what is now known as type 1 diabetes and type 2 diabetes was first clearly made by Sir Harold Percival (Harry) Himsworth, and published in January 1936.
Identification of the first of the sulfonylureas in 1942

Use of biguanides for Type 2 diabetes in the late 1950s.
The initial phenformin was withdrawn worldwide (in the U.S. in 1977) due to its potential for sometimes fatal lactic acidosis.

Metformin was first marketed in France in 1979, but not until 1994 in the US.

The determination of the amino acid sequence of insulin by Sir Frederick Sanger, for which he received a Nobel Prize)

The radioimmunoassay for insulin, as discovered by Rosalyn Yalow and Solomon Berson
Dr Gerald Reaven's identification of the constellation of symptoms now called metabolic syndrome in 1988
Identification of the first thiazolidinedione as an effective insulin sensitizer during the 1990s
In 1980, U.S. biotech company Genentech developed human insulin. The insulin is isolated from genetically altered bacteria (the bacteria contain the human gene for synthesizing human insulin), which produce large quantities of insulin.

03 May, 2010


Hi Friends,
I am Dr.Riyaz. I completed my M.B.B.S from Yenepoya Medical College in Mangalore and currently working in M.V Centre for Diabetes in Chennai. I always felt the need that we need a forum to clear our doubts on Diabetes ( even the silliest ones!) that's the reason I have created this blog.