The figure could rise to 70 million by 2025. Diabetes is the fastest-growing disease in the world, with 230 million people already affected. It is the world’s leading cause of heart disease, stroke, blindness, kidney disease and lower limb amputation. The incidence of Diabetes is five times higher among Asians than it is in western population.

Risk factors of diabetes are when their pancreas gets destroyed due to an accident or injury. Family history, Obesity, Lake of exercises, Luxurious life style, Fast food, Smoking and alcohol drinking, Mental Stress are also other factors.

Warning Signs of diabetes are Extreme thirst, frequent urination, Constant hunger, Blurred vision, sudden weight loss, Nausea & vomiting, Infections & extreme tiredness, Feeling tired and lethargic, Slow-healing wounds, Itching and skin infections and Mood swings.

Prevalence and Incidence:

· More than 180 million adults were living with diabetes globally¹

· In 2003, the total was 194 million²

· By 2030, the figure is expected to rise to 366 million³

· Type 2 diabetes accounts for approximately 90 percent of all diabetes cases¹

· Two people develop diabetes every ten seconds⁴

· One in three Americans born today will develop type 2 diabetes in their lifetime⁵

· At least 50 percent of all people with diabetes are unaware of their condition. In some countries this figure may reach 80 percent⁴

· Up to 80 percent of type 2 diabetes is preventable by adopting a healthy diet and increasing physical activity⁴

· The highest rate of diabetes prevalence is in North America (9.2 percent) followed by Europe (8.4 percent)²

· In 2007, the five countries with the largest numbers of people with diabetes were in India 40.9 million;China 39.8 million, United States 19.2 million and Russia had 9.6 million patients of diabetes⁴.

Mortality and Complications:

· Every 10 seconds a person dies from diabetes-related causes⁴

· Diabetes is the fourth leading cause of global death by disease⁴.Each year diabetes accounts for 3.8 million deaths⁴

· An even greater number die from cardiovascular disease made worse by diabetes-related lipid disorders and hypertension⁴

· Diabetes is responsible for approximately six percent of total global mortality, about the same as HIV/AIDS⁶

· The total number of diabetes deaths is expected to increase by more than 50 percent over the next decade¹

· Cardiovascular disease is the major cause of death in diabetes, accounting for approximately 50 percent of all diabetes fatalities¹

· On average, people with type 2 diabetes will die 5-10 years before people without diabetes⁴

· People with type 2 diabetes are more than twice as likely to have a heart attack or stroke as people who do not have diabetes⁴

· 10 to 20 percent of people with diabetes die of renal failure¹

· More than 2.5 million people worldwide are affected by diabetic retinopathy – the leading cause of vision loss in adults of working age in industrialized countries⁴

Economic Burden:

· In 2007, the world spent at least US$ 232 billion to treat and prevent diabetes and its complications⁶By 2025, this lower-bound estimate will exceed US$ 302.5 billion⁶

· $555.7 billion in lost national income in China over the next 10 years, $303.2 billion in the Russian Federation, $333.6 billion in India, $49.2 billion in Brazil, $2.5 billion even in a very poor country like Tanzania

· By 2025, the largest increases in diabetes prevalence will take place in developing countries⁴

· Almost 80 percent of diabetes deaths occur in low and middle-income countries¹

· In India, the poorest people with diabetes spend an average of 25 percent of their income on private care⁶

· More than 80 percent of expenditures for medical care for diabetes are made in the world’s economically richest countries⁶

· Less than 20 percent of expenditures are made in the middle- and low-income countries, where 80 percent of people with diabetes will soon live⁶

· The United States is home to about 8 percent of diabetes patients but spends more than 50 percent of all global expenditure for diabetes care⁶

· Europe accounts for another quarter of spending on diabetes care⁶

· The disparity in spending for diabetes care between the industrialized countries and the rest of the world continues to increase⁶

Diagnosis:

The World Health Organization definition of diabetes is for a single raised glucose reading with symptoms, otherwise raised values on two occasions, of either:⁷

Fasting plasma glucose ≥ 7.0 mmol/l (126 mg/dl)

With a Glucose tolerance test, two hours after the oral dose a plasma glucose ≥ 11.1 mmol/l (200 mg/dl)

The targets are:

HbA1c of 6%²⁵to 7.0%⁸

Pre-prandial blood glucose: 4.0 to 6.0 mmol/L (72 to 108 mg/dl)⁹

2-hour postprandial blood glucose: 5.0 to 8.0 mmol/L (90 to 144 mg/dl)⁹

Emerging targets for diabetes:

The role of peroxisome proliferator activated receptors (PPARs) in the regulation of lipid metabolism, insulin and triglycerides leads to the rational design of several PPAR agonists. Two targets like protein tyrosine phosphatase 1B (PTP-1B) and glycogen synthase kinase-3 (GSK-3), have emerged as validated targets for treating this disease. GSK-3 inhibitors which plays a key role in the insulin signalling pathway, has been intensely studied by various companies as a potential target for the development of Antidiabetic therapies.

Inhibitors of PTP-1B:

Protein tyrosine phosphatase-1B Tyrosine phosphorylation of proteins is a fundamental mechanism for the control of cell growth and differentiation. It is reversible process which governed by the opposing activities of protein tyrosine kinases (PTKs), which catalyse phosphorylation and protein tyrosine phosphatase (PTPs), which are responsible for dephosphorylation¹⁰.

Defective or inappropriate operation of these network leads to aberrant tyrosine phosphorylation, contributing to the development of many diseases like cancer and diabetes. PTPs can be divided into three major subfamilies – tyrosine-specific, dual-specific and low molecular weight phosphatase. The dual-specific phosphatase utilizes the protein substrate that contains pTyr as well as pSer and pThr¹¹.

Phosphatase LAR, CD45, SHP-2, cdc25c and T-cell PTP (TCPTP) share 50–80% homology in the catalytic domain with PTP-1B, which presents a challenging task of achieving selectivity, especially over T-cell PTP. Thus it was necessary for the inhibitors to interact with the regions outside the catalytic site in order to be selective. A non-catalytic phosphotyrosine-binding site was identified, which seems to be ideal since it is close to the catalytic site and is less homologous between the PTP-1B and T-cell PTP when the amino acid sequences were compared. Hence targeting both the sites simultaneously may show good activity and selectivity against PTP-1B.

Vanadium inhibits phosphotyrosine phosphatase and activates autophosphorylation of tyrosine residue. Vanadium has lack specificity and augments tyrosine phosphorylation of a wide variety of cellular proteins. They pose toxicity problems as they also target some ATPase, adenylate cyclase and Ca²⁺ channels.¹²

High throughput screening identified 1, 2-naphthoquinones as the lead molecule having IC50 values in micro-molar range. The derivatives of 1, 2-naphthoquinone (1) were evaluated for their in vitro inhibitory activity against recombinant human PTP-1B using fluorescein diphosphate.

In this series, 4-cyclohexyl-1, 2-naphthoquinone exhibited 10 to 60-fold selectivity over other PTPs18. Pyridazine analogues are reversible, non-competitive PTP-1B inhibitors. This indicates that they do not bind within the active site cleft of PTP-1B. High throughput screening showed compound (2) derivatives as being novel reversible inhibitors with an IC50 value in micro-molar range.

Unlike many tyrosine phosphatase inhibitors, this compound class lacks negative charge and thus showed high permeability across the cell membrane. The non-peptidyl compounds having difluoromethylene phosphonic acid (DFMP) group were shown to be potent inhibitors of PTP-1B. The phenyl or ethynyl group at Meta position increases potency by 15 to 17-fold. The increase is due to the pi–cation interaction of the phenyl ring with Lys-116 and Lys-120. The a, b-unsaturated allyl ester (3) moiety was the most potent reversible, competitive inhibitor¹³.

3-Formylchromone is a neutral molecule and inhibits PTP-1B with potency of 73 mM. 6-Biphenyl-3-formylchromone (4) was found to be the most potent inhibitor in this series. It is suggested to have extended interaction of the extra phenyl ring with the surface near the active site of the enzyme¹⁴.

Oxalyl-arylamino benzoic acid derivatives are catalytic site-directed, competitive and reversible PTP-1B inhibitors. The dicarboxylic acid portion of the molecule binds in the catalytic site; compound was found to be the most potent in this series. The S-isomer is 20-fold more active than the R-form¹⁵. The oxamyl propionic acid analogue also has selectivity over T- cell PTP.

As the number of acid groups increases, the chance for the inhibitor to penetrate the cell membrane via passive diffusion is dramatically reduced. The monoacid analogue has maintained most of the potency of the corresponding diacid and has selectivity greater than 23-fold over T- cell PTP.

The phosphopeptide Ac–Asp–Ala–Asp–Glu–Xxx–Leu– NH2 (5), derived from epidermal growth factor receptor is an excellent substrate for PTP-1B, when Xxx represents pTyr. But the major limitation of pTyr-containing peptides is their susceptibility to phosphorolysis and inactivation by PTPs. Since the phosphate group is crucial for PTP substrate binding, an effective, non-hydrolysable phosphate mimetic is an important aspect of PTP-1B inhibitor design.

The most effective phosphate mimetic reported is the DFMP group. Peptide-bearing phosphono (di-fluoromethyl) phenylalanine (F2Pmp) binds better than the analogue peptide substrates and can be up to three orders of magnitude more effective than the non-fluorinated analogues. But the dianionic nature of the DFMP group compromises cell permeability¹⁶.

As the efficacy of the phosphonates is hampered by their inability to penetrate into cells, there is considerable interest in the development of non-phosphorus containing pTyr mimetics. The analogues that utilize the dicarboxylic acid-containing malonate structure as phosphate isosteres are the most successful non-phosphorus containing pTyr mimetics. These include O-malonyltyrosine (OMT) and fluoro-O-malonyltyrosine (FOMT), which in the context of peptides are among the most potent PTP-1B inhibitors.

They are designed to potentially afford pro-drug protection strategies. It was envisioned that the charged malonyl carboxyl groups could be masked in their ester form, and then liberated once inside the cells to the free carboxyls via the action of cytoplasmic esterase. The limitation of OMT-containing peptide is the removal of only one esterafter esterase treatment.

Peptides containing dicarboxylicacid-based pTyr mimetics were prepared and evaluated for their PTP-1B inhibitory potency¹³.

O-Malonyl tyrosine and O-carboxymethyl salicylic acid containing peptides are found to be potent inhibitor of PTP-1B. Both were effective at enhancing the insulin stimulated uptake of 2-deoxyglucose by L6 myocytes¹⁴. Aryl a-ketocarboxylic acids comprise a new class of inhibitors for PTP-1B. The peptide containing phenyl glyoxalic acid (6) has shown some promise against PTP-1B.

Figure 3: Chemical structures of Sitagliptin and Vildagliptin

But these peptides are not as potent as other peptides containing FOMT and F2Pmp. However, they have better activity than peptides with pTyr analogue having a single carboxylic acid. Alpha-bromoacetophenone derivatives act as potent PTP inhibitors by covalently alkylating the conserved catalytic cysteine in the PTP active site. Derivatization of the phenyl ring with a tripeptide Gly–Glu–Glu29 resulted in potent, selective inhibitors against PTP-1B.

GSK-3 inhibitor:

GSK-3 inhibitors impact on signalling pathways. GSK-3 inhibitors lower blood glucose level by acting three distinct regions to suppress enzyme activity: (I) metal ion (Mg2+) binding site; (ii) substrate interaction domain, and (iii) ATP-binding pocket¹⁷.

Lithium salts (Li+) weakly inhibit GSK-3 through competition with the binding of Mg^2+, the essential metal ion cofactor of the enzyme^{18, 19}.

Inhibition of GSK-3 by lithium salts causes enhanced glycogen synthase activity and reduced phosphorylation of various GSK-3 substrates. Based on the mechanism phosphorylation at Ser-9/Ser-21 several phosphopeptides, derived from the amino-terminal end of GSK-3b, have been produced in an effort to compete with the binding of substrates to the phosphate interaction site of the enzyme. One such phosphopeptide, Thr–Thr–pSer–Phe–Ala–Glu–Ser–Cys, was found to inhibit the phosphorylation of glycogen synthase.

Using the screening programmes specifically aimed at finding GSK-3 inhibitory activity in compounds which reported with other biological properties like hymenialdisine, paullones, indirubins and maleimides were picked up^20-23.

High throughput screening of the SmithKline Beecham compound collection has identified 3-anilino-4-arylmaleimide (7) as potent GSK-3 inhibitors. Pharmacological studies conducted on maleimide derivatives, SB-216763 (8) and SB-415286 (9), have shown that they stimulated glycogen synthesis in human liver cells. SB-517955 had the capacity to lower glucose level in animal models.

Johnson and Johnson Pharmaceutical Research and Development developed a novel series of macrocyclic bisindolylmaleimidescontaining linkers with multiple heteroatoms having high selectivity for GSK-3b. Another series developed by Johnson and Johnson is polyoxygenated bis-7-azaindolyl maleimides^24-26.

Glaxo SmithKline Research and Development afforded a series of pyrazolo [3, 4-b] pyridines (10) and pyrazolo [3, 4- b] pyridazines with IC50 value in nM range. Novo Nordisk reported the discovery of GSK-3 inhibitory activity within various chemical series, including substituted oxadiazepines²⁷.1-(4-amino-1, 2, 5-oxadiazolyl)-1, 2, 3- triazole derivatives ^{28, 29} and 2, 4-diaminothiazoles (11, 12)^{30, 31}. Vertex Pharmaceuticals described the preparation of 4-arylpyrimidine-2-amines (13)^32,33 and 4,5 dihydro- 1H-pyrazole-5-one (14)³⁴ as GSK-3 inhibitors. Their potential in treatment of type 2 diabetes is still to be evaluated.

Chiron Corporation claimed the discovery of several GSK-3 inhibitors comprising substituted 2-aminopyridazines (16)³⁵, 2-aminopyrimidines³⁶ WO 02/020495 and 2-aminopyridines72 WO 99/065897. CT-98023 (15) developed by Chiron has shown good oral bioavailability, which reduced plasma glucose levels in fasted hyperglycemic rats, improved hyperglycemia and glucose disposal in diabetic mice³⁷

Dipeptidyl Peptidase (DPP)-IV Inhibitor:

Dipeptidyl peptidases (DPP)-IV inhibitors, which act via enhancing the incretins, represent another new therapeutic approach to the treatment of type 2 diabetes.

Glucagon-like peptide 1 and glucose dependent insulin tropic peptide (GIP) account for the majority of incretin action. GLP-1 is a gut hormone that plays a key role in glucose homeostasis via its incretin effect. GLP-1 is produced from the enteroendocrine L-cell of small intestine and is secreted in response to meal and nutrients. It stimulates insulin release from the pancreatic islets in a glucose dependent manner. It restores the defective first and second phases of insulin response to glucose in type 2 diabetes patients^{38, 39}.

GLP-1 suppresses post-prandial glucagon release, delay gastric emptying and increase satiety. In animal models, GLP-1 and its analogs are shown to stimulate beta-cell proliferation and differentiation. These may help in preserving the pancreatic beta cell mass and function, and thus have beneficial effect in the prognosis of type 2 diabetes. GLP-1 has a very short half-life. It is rapidly degraded inside our body by the enzyme Dipeptidyl peptidase (DPP)-IV. Therapeutic agents which block the DPP-IV enzyme can increase the endogenous GLP-1 level and thus enhances the incretin action.

Sitagliptin is a potent and highly selective DPP-IV inhibitor. It is the first from this novel class of oral antihyperglycaemic agent that has been approved by the United States (US) FDA in October 2006 for the treatment of type 2 diabetes. It can be used as a monotherapy or in combination with metformin or thiazolidinedione. Sitagliptin is orally active and can be administrated once daily. A single oral dose of Sitagliptin 100mg can inhibit plasma DPP-IV activity 80% over 24 hours of time. By slowing incretin degradation, Sitagliptin increases meal-stimulated active GLP-1 level to two to threefold, leading to increase in insulin and C-peptide levels, reduction in plasma glucagon levels, reduction in post-prandial glucose excursion and better glycemic control in type 2 diabetes patients.

A 24-week randomised, double-blinded, placebo-controlled study in type 2 diabetes patients demonstrated that Sitagliptin 100mg daily monotherapy improved fasting and postprandial glycemic control, reduced HbA1c by 0.79% (p<0.001), improved beta-cell function, with neutral effect on body weight, similar incidence of hypoglycemia, slightly higher overall gastrointestinal adverse experiences when compared with placebo.

Patients with baseline HbA1c 9% had greater reductions in placebosubstracted HbA1c (-1.52%) than those with baseline HbA1c <9%17.

DPP-IV inhibitor had been shown to improve beta cell function in patients and animal models with type 2diabetes. In animal models, DPP-IV inhibitor can lead to beta cell neogenesis and survival^{40, 41}.

Nonetheless, long term clinical studies are required to see whether similar beta cell effects are found in patients with type 2 diabetes. Vildagliptin is another DPP-IV inhibitor which acts via similar mechanism as Sitagliptin but has not yet been approved by US FDA. In summary, DPP-IV inhibitors is a novel class of oral hypoglycemic agent with potentials in improving pancreatic beta cell function and the clinical course of type 2 diabetes.

Physiological Functions of GLP-1:

Stimulates insulin secretion, glucose-dependently, Increases b-cell mass in animal models, Decreases glucagon secretion, glucose-dependently, Delays gastric emptying, decreases food intake and body weight, Improves insulin sensitivity; enhances glucose disposal, Has a beneficial cardiovascular effect, Has a beneficial CNS effect in animal models.

Use of nanotechnology in the detection of insulin and blood sugar:

A new method that uses nanotechnology to rapidly measure amounts of insulin and blood sugar level which is a major step for developing the ability to assess the health of the body’s insulin-producing cells. It can be achieved by microphysiometer and by implantable sensor.

Microphysiometer:

The microphysiometer which is built from multiwalled carbon nanotubes, which are prepared by several flat sheets of carbon atoms stacked and rolled into very small tubes. The nanotubes are electrically conductive and the concentration of insulin in the chamber can be directly related to the current at the electrode and the nanotubes operate reliably at pH levels characteristic of living cells. The detection methods measure insulin production at intervals by periodically collecting small samples and measuring their insulin levels. The insulin levels can detect by sensor continuously by measuring the transfer of electrons produced when insulin molecules oxidize in the presence of glucose. When the cells produce more insulin molecules, the current in the sensor increases and vice versa, allowing monitoring insulin concentrations in real time.⁴²

Implantable sensor:

Use of polyethylene glycol beads coated with fluorescent molecules to monitor diabetes blood sugar levels is very effective method. This method the beads are injected under the skin and stay in the interstitial fluid. When glucose in the interstitial fluid drops to dangerous levels, glucose displaces the fluorescent molecules and creates a glow. This glow is seen on a tattoo placed on the arm. Sensor microchips are also being developed to continuously monitor key body parameters including pulse, temperature and blood glucose. A chip would be implanted under the skin and transmit a signal that could be monitored continuously.

Use of Nanotechnology in the treatment of diabetes:

The stomach acid destroys protein-based Insulin. Diabetic patients control their blood-sugar levels via insulin introduced directly into the bloodstream by injections which is very painful. The new system is based on inhaling the insulin and on a controlled release of insulin directly into the bloodstream. Such kind of treatment for diabetes includes the proper delivery of insulin in the blood stream it can be achieved by nanotechnology by development of oral insulin.

Production of pharmaceutically active proteins, such as insulin, in large quantities has become feasible ^{43, 44}^. The oral route is considered to be the most safe and comfortable means for administration of insulin for less expensive and painless diabetes management, leading to a higher patient compliance ^45.

The intestinal epithelium is a major barrier to the absorption of hydrophilic drugs, as they cannot diffuse across epithelial cells through lipid-bilayer cell membranes to the bloodstream ⁴⁶^. Therefore, attention has been given to improving the paracellular transport of hydrophilic drugs^{47, 48.}

A variety of intestinal permeation enhancers including chitosan (CS) have been used for the assistance of the absorption of hydrophilic macromolecules^.Therefore, a carrier system is needed to protect protein drugs from the acidic environment of stomach if it given orally⁴⁹^. Chitosan nanoparticles (NPs) increase the intestinal absorption of protein molecules to a greater extent than aqueous solutions of CS in vivo⁵⁰^. The insulin loaded NPs coated with mucoadhesive CS may prolong their residence in the small intestine, infiltrate into the mucus layer and subsequently mediate transiently opening the tight junctions between epithelial cells while becoming unstable and broken apart due to their PH sensitivity and/or degradability. The insulin released from the broken-apart NPs could then permeate through the paracellular pathway to the bloodstream, its ultimate destination.

Microsphere for oral insulin production:

The most promising strategy to achieve oral insulin is the use of a microsphere system which is inherently a combination strategy. Microspheres act both as protease inhibitors by protecting the encapsulated insulin from enzymatic degradation within its matrix and as permeation enhancers by effectively crossing the epithelial layer after oral administration.⁵¹

Artificial Pancreas:

Development of artificial pancreas could be the permanent solution for diabetic patients. The original idea was first described in 1974. The concept of its work is simple: a sensor electrode repeatedly measures the level of blood glucose; this information feeds into a small computer that energizes an infusion pump, and the needed units of insulin enter the bloodstream from a small reservoir.⁵²

Another way to restore body glucose is the use of a tiny silicon box that contains pancreatic beta cells taken from animals. The box is surrounded by a material with a very specific nanopore size which has about 20 nanometers in diameter. These pores are big enough to allow for glucose and insulin can easily pass through them, but small enough to impede the passage of much larger immune system molecules. These boxes can be implanted under the skin of diabetes patients. This could temporarily restore the body’s delicate glucose control feedback loop without the need of powerful immunosuppressant that can leave the patient at a serious risk of infection⁵³. Scientists are also trying to create a nanorobot which would have insulin departed in inner chambers, and glucose level sensors on the surface. When blood glucose levels increase, the sensors on the surface would record it and insulin would be released. Yet, this kind of nano-artificial pancreas is still only a theory ⁵⁴.

The Nanopump:

The nanopump is a powerful device and has many possible applications in the medical field. The first application of the pump, introduced by Debiotech, is Insulin delivery. The pump injects Insulin to the patient's body in a constant rate, balancing the amount of sugars in his or her blood. The pump can also administer small drug doses over a long period of time ⁵⁵.

In the foreseeable future, the most important clinical application of nanotechnology will probably be in pharmaceutical development. These applications take advantage of the unique properties of nanoparticles as drugs or constituents of drugs or are designed for new strategies to controlled release, drug targeting, and salvage of drugs with low bioavailability. Hopefully, the new kind of treatment may help in making the everyday lives of millions of diabetes patients more tolerable. The application of nanotechnology to medicine is called nanomedicine. Nanomedicine subsumes three mutually overlapping and progressively more powerful molecular technologies: nanoscale structured materials and devices; genomics, proteomics and artificial engineered microbes; and medical nanorobots ⁵⁶.

Stem cell research for diabetes:

Adult cells successfully treat humans with diabetes.2005 Islet cells can be donated from live donors for patients, opening up many more transplant possibilities. Using this technique, a mother donated cells for her diabetic daughter alleviating the diabetic symptoms. Matsumota S et al., Insulin independence after living-donor distal pancreatectomy and islet allotransplantation.

2001 The Edmonton protocol was used to isolate cadaveric islet cells to treat 12 people with juvenile diabetes.

Ryan A. et al., Glycemic Outcome Post Islet Transplantation, Annual Meeting of the American Diabetes Association, June 22-26, 2001. Since 2001, over 200 diabetic patients have been treated with this protocol.

2006 Tulane researchers showed that human bone marrow adult stem cells restored normal insulin secretion and blood sugar in mice, and promoted repair of both pancreas and kidney tissue.

2006 Three independent studies confirmed earlier findings by Harvard researchers that blocking autoimmune attack on the diabetic pancreas leads to regeneration of insulin-secreting cells in diabetic mice.

2006 NIH scientists showed that they could grow pancreatic cells for long periods and turn them into insulin-secreting cells. The defined combination of growth factors controls generation of long-term replicating islet progenitor-like cells from cultures of adult mouse pancreas⁵⁷. 2006 A Japanese team demonstrated that human umbilical cord blood stem cells could form insulin-secreting cells⁵⁸.

2005 Israeli scientists have found that patients could serve as their own donors, converting their liver cells to insulin-secreting cells⁵⁹

2004 University of Florida researchers restored normal blood sugar levels in diabetic mice for three months by transforming bone marrow stem cells into islet-like cells that produced normal insulin levels⁶⁰.

2002 University of Florida researchers turned liver stem cells into pancreatic cells. When implanted into mice, these transformed cells reversed hyperglycemia in 10 days. Yang L. et al., In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone producing cells.

2005 Embryonic stem cells briefly reversed hyperglycemia in mice, but caused tumors. Fujikawa T et al., Teratoma formation leads to failure of treatment for type I diabetes using embryonic stem cellderived insulin-producing cells.⁶¹

2004 Scientists found that what appeared to be insulin-producing cells differentiated from embryonic stem cells did not actually make insulin, and formed tumors.

2004 Scientists in Israel produced clusters with some insulin-secreting cells from embryonic stem cells. Segev H et al., Differentiation of human embryonic stem cells into insulin-producing clusters.

2003 Repeat of previous studies showed that embryonic stem cells did not make insulin. Rajagopal J et al., Insulin staining of ES cell progeny from insulin uptake,

2002 A study showed embryonic stem cells turned into a kind of insulin-producing cell, not beta cells, that produced 13% of the normal insulin levels. When injected, the mice were kept alive but not enough to cure the diabetes.

Hori Y, et al., Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells.

2001 Media-heralded study showed that embryonic stem cells turned into pancreatic cells. In fact, the cell made only 1/50 the normal amount of insulin and the mice died.

Insulin pump therapy:

An insulin pump is new small device like pager which delivers small amounts of insulin continuously around the clock. This gives you more stable blood sugar than with insulin pen. So it is very useful to diabetic patients who administer injections every day. With the pump patients are free to decide when to eat, sleep or exercise.

Insulin pump therapy can lead to major improvements in blood glucose control and offers a higher standard for diabetes management.⁶² optimal blood glucose control provides them with the flexibility to pursue an active lifestyle while still attending to their diabetes needs.

The best control can often seem like a balancing act between food, insulin and activity. There is a higher risk of severe hypoglycemia when you try to tighten their control using injections.⁶³

Therefore with an insulin pump, patients don’t have to follow a strict schedule; they can have better control without compromise.

Insulin pump therapy is proven to improve quality of life. Users report fewer daily challenges, more flexibility and less worry about the future. This corresponds to the fact that up to 97% of people who change to an insulin pump don’t go back to injections.⁶⁴

Working of insulin pump:

A Medtronic MiniMed insulin pump is about the size and weight of a pager. It has a small cartridge called a “reservoir” inside that holds up to three days’ worth of insulin. A battery provides power to a computer chip that acts as the insulin pump’s brain. It controls how much insulin the pump delivers.

Instead of using a syringe and needle to deliver insulin, the pump uses an infusion set with a tiny, soft plastic tube called a “cannula”.

This cannula comfortably lies just beneath your skin. The infusion set is generally worn for two to three days at a time and then replaced. Patients can comfortably disconnect the pump and infusion set from there body while shower, change clothes or play sports.

The small insulin pump is easy and discreet to wear. They can attach the pump to there belt or place it in pocket or under clothing. An insulin pump is worn externally. A tiny, plastic tube called a “cannula” lies just beneath to skin to deliver insulin from the pump into body. Soft, flexible tape holds the cannula in place.

An insulin pump is proven to achieve better control than injections, with less risk of severe hypoglycemia. Type 2 diabetic patients who switch from injections to an insulin pump have found it easier to achieve recommended HbA1c target levels.^{65,
66, 67, and 68}

Glossary of insulin pumps:

Basal rate: the small, continuous dosing of regular or rapid-acting insulin to keep blood glucose steady when patients are not eating. Since they can adjust basal insulin for different times of the day, an insulin pump can more closely mimic a healthy pancreas. For example, when they sit at desk, patients can program the insulin pump to automatically give more insulin than when they doing exercise at the gym.

Bolus dose: a larger dose of insulin taken with food or to correct high blood glucose.

Infusion set: the soft, flexible tubing and cannula that delivers insulin from the pump to body. They generally wear an infusion set for two to three days at a time.

Rapid-acting insulin: a type of insulin that generally starts working within 15 minutes and can last up to five hours.

Reservoir: the cartridge inserted into the pump that holds up to three days’ worth of insulin.

Intensive management can reduce the risk of complications:

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive management of glucose levels in Type 1 patients reduces HbA1c, which in turn reduces the risk of complications: ⁶⁹

• Retinopathy by up to 76 %.

• Nephropathy by up to 56%.

• Neuropathy by 69%.

Numerous clinical studies demonstrate the most effective method of intensive management for diabetes is insulin pump therapy. One report revealed a six-fold reduction in severe hypoglycemic events for patients who switched from multiple injections to an insulin pump.⁷⁰

Pump therapy is not recommended for people who are unwilling or unable to perform a minimum of four blood glucose tests per day and to maintain contact with their healthcare professional. Successful operation of an insulin pump requires good vision and hearing.

REFERENCES:

1. World health organization. Fact sheet no. 312: what is diabetes? Available at: Http://www.who.int/mediacentre /factsheets/fs312/en/.Accessed on: 14 October, 2008.

2. International diabetes federation. Diabetes prevalence. Available at: http://www.idf.org/home/index.cfm?Node=264. Accessed on: 14 October, 2008.

3. World health organization. Diabetes action now booklet. Available at: Http://www.who.int/diabetes/booklet_html /en/print.html. Accessed on: 14 October, 2008.

4. International diabetes federation. Facts & figures: did you know? Available at: Http://www.idf.org/home/index. cfm?Unode=3b96906bc026-2fd3-87b73f80bc22682a. Accessed on: 14 October, 2008.

5. American diabetes association. 1 in 3 Americans born in 2000 will develop diabetes. Available at: Http://www.diabetes.org/for-media/scientific-sessions/06-14-03-2.jsp. Accessed on: 14 October, 2008.

6. International diabetes federation. The human, social and economic impact of diabetes.

7. World health organization. "definition, diagnosis and classification of diabetes mellitus and its complications: report of a who consultation. Part 1. Diagnosis and classification of diabetesmellitus". Http://www.who.int/ diabetes/publications/en/. Retrieved on 2007-05-29.

8. Qaseem A, Vijan S, Snow V, Cross JT, Weiss KB, Owens DK (September 2007). "glycemic control and type 2 diabetes mellitus: the optimal hemoglobin a1c targets. A guidance statement from the american college of physicians". Ann. Intern. Med. 147(6): 417–22. Pmid 17876024. Http://www.annals.org/cgi/content/full/147/6/417. Retrieved on 2008-07-19.

9. "clinical practice guidelines" http://www.diabetes.ca /cpg2003/chapters.aspx. Retrieved on 2008-07-19.

10. Leung C. et al., The difluoromethylenesulfonic acid group as a monoanionic phosphate surrogate for obtaining PTP-1B inhibitors. Bioorg. Med. Chem., 2002, 10, 2309–2323.

11. Zhang ZY, Protein tyrosine phosphatases: prospects for therapeutics. Curr. Opin. Chem. Biol., 2001, 5, 416–423.

12. Huijsduijnen VRH, Bombrun A, and Swinnen D, Selecting protein tyrosine phosphatases as drug targets. Drug Discovery Today, 2002, 7, 1013–1019.

13. Masiello P, Broca C, Gross R, Roye M, Manteghetti M, Hillaire-Buys D, Novelli M, Ribes G. Diabetes 1998, 47, 224.

14. Ortiz-Andrade RR, Rodrı´guez-Lo´pez V, Gardun˜o- Ram´ırez ML, Castillo-Espan˜a, P, Estrada-Soto SJ. Ethnopharmacol. 2005, 101, 37.

15. Chemical Computing Group Inc., 1255 University Street, Montreal, Quebec, Canada H3B 3X3, 2005. Molecular Operating Environment (MOE). http://www.chemcomp.com.

16. Website: http://www.ibmh.msk.su/PASS .

17. Wauwe JV, and Haefner B, Glycogen synthase kinase-3 as drug target: From wallflower to center of attention. Drug News Perspect. 2003, 16, 557–565.

18. Ryves WJ, and Harwood AJ, Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem. Biophys. Res. Commun., 2001, 280, 720–725.

19. Zhang F, Christopher JP, Laura S, Nadia G, and Klein PS, Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium. J. Biol. Chem., 2003, 278, 33067–33077.

20. Kunick C, Lauenroth C, Wieking K, Schultz C, Lemcke T, and Flemming SJ, Evaluation and comparison of 3D-QSAR CoMSIA models for CDK1, CDK5 and GSK-3 inhibition by paullones. J. Med. Chem., 2004, 47, 22–36.

21. Kunick C, Lauenroth C, Leost M, Meijer L, and Lemcke T, 1-Azakenpaullone is a selective inhibitor of glycogen synthase kinase-3b. Bioorg. Med. Chem. Lett., 2004, 14, 413–416.

22. Meijer L, Skaltsounis A, Magiatis P, and Knockaert M, GSK- 3 selective inhibitors derived from Tyrian purple indirubins. Chem. Biol., 2003, 10, 1255–1266.

23. Smith DG, Buffet M, Ashley EF, Haigh D, Ife RJ, and Ward RW., Macrocyclic bisindolylmaleimides as inhibitors of protein kinase C and glycogen synthase kinase-3. Bioorg. Med. Chem. Lett., 2003, 13, 3049–3053.

24. Gee-Hong K, Prouty C, Angelis AD, Shen L, ONeill DJ, Shah C. and Jolliffe L, Synthesis and discovery of macrocyclicpolyoxygenatebis-7-azaindolylmaleimides as a novel series of potentand highly selective glycogen synthase kinase-3b inhibitors.J. Med. Chem., 2003, 46, 4021–4031.

25. Shen, L, Prouty, C, Conway BR., Jun, ZX. and Gee-Hong K., Synthesis and biological evaluation of novel macrocyclic bis-7-azaindolylmaleimides as potent and highly selective glycogen synthasekinase-3b (GSK-3b) inhibitors. Bioorg. Med. Chem., 2004, 12, 1–1

26. Zhang, HC., Ye H., Conway B R., Derian CK. and Maryanoff BC., 3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitorsof glycogen synthase kinase-3. Bioorg. Med. Chem. Lett., 2004, 14, 3245–3250.

27. Bowler AN., Kilburn JP., Engelhardt S., Danielsen GM. and Kurthzals P., Oxadiazepines with glucose lowering properties. 16th Int. Symp. Med. Chem., 2000, www.google.com

28. Olesen P, Kurthzhals P., Worsaee H, Hansen BF, Sorensen AI. and Bowler A. N., Synthesis and in vitro characterization of 1-(4-aminofurazan-3-yl)-5-dialkylamino methyl-1H-[1, 2, 3] triazole-4- carboxylic acid derivatives. J. Med. Chem., 2003, 46, 3333–3341.

29. Olesen P, Kurthzhals P, Worsaee H., Hansen, B. F., Sorensen, A. I. and Bowler, A. N., Furazanyl-triazole derivatives for the treatment of diseases. 2002, WO 02/032896.

30. Sorensen AR., Worsaae H., Hansen BF, Kurthzhals P, Bowler AN, and Olesen PH, 2, 4-Diaminothizole derivatives and their use as glycogen synthase kinase-3 (GSK-3) inhibitors. 2001, WO 01/056567.

31. Bowler AN, and Hansen BF, 2, 4-Diaminothiazole derivatives and their use as glycogen synthase kinase-3 (GSK-3) inhibitors. 2003, WO 03/011843.

32. Cochran J., Nanthakumar J., Harrigton E. and Wang J., Thiazole derivatives useful as inhibitors of protein kinases. 2002, WO 02/096905.

33. Moon YC, Green J, Davies R, Choquette D, Pierce A, and Ledeboer M, 5-(2-aminopyrimidine-4-yl) benzisoxazoles as protein kinase inhibitors. 2002, WO 02/102800.

34. Green J, Arnost MJ, and Pierce A, Pyrazolone derivatives as inhibitors of GSK-3. 2003, WO 03/011287.

35. Savithri R. and Nuss J., Pyrazine based inhibitors of glycogen synthase kinase-3. 2001, WO 01/044206.

36. Desai M., Ramurthy S, Nuss J M. and Boyce R, Pyrimidine based inhibitors of GSK-3. 2002, WO 02/020495.

37. Cline GW. et al., Effects of novel glycogen synthase kinase-3 inhibitors on insulin stimulated glucose metabolism in zucker diabetic fatty (fa/fa) rats. Diabetes, 2002, 51, 2903–2910.

38. Fehse F, Trautmann M, Holst JJ, Halseth AE, Nanayakkara N, Nielsen LL, et al. Exenatide augments first- and second-phase insulin secretion in response To intravenous glucose in subjects with type 2 diabetes. J clin endocrinol metab 2005; 90(11):5991-7. Epub 2005 Sep 6.

39. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 1993; 36(8):741-4.

40. Pospisilik JA, Martin J, Doty T, Ehses JA, Pamir N, Lynn FC, et al. Dipeptidyl Peptidase iv inhibitor treatment stimulates beta-cell survival and islet Neogenesis in streptozotocin-induced diabetic rats. Diabetes 2003; 52(3):741-50.

41. Mu J, Woods J, Zhou YP, Roy RS, Li Z, Zycband E, et al. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic{beta}-cell mass and function in a rodent model of type 2 diabetes. Diabetes 2006; 55(6):1695-704.

42. Microphysiometer using multiwall carbon nanotubes enables constant realtime monitoring of microliters of insulin [electronic resource] [accessed 2008 apr 18].Available from: URL: http://nextbigfuture.com/2008/04/microphysiometer-using-multiwall carbon.html

43. Liang HF, Hong MH, Ho RM, Chung CK, Lin YH, Chen CH and Sung HW. Novel method using a temperature-sensitive polymer (methylcellulose) to thermally gel aqueous alginate as a ph-sensitive hydrogel biomacromolecules 5, 1917– 25(2004).

44. Smyth s and heron a. Diabetes and obesity: the twin epidemics nat. Med. 12, 75– 80 (2006)

45. Krauland AH, Guggi D and Bernkop-Schn¨urch A. Oral insulin delivery: the potential of thiolated chitosan-insulin tablets on non-diabetic rats j. Control. Release 95, 547– 55(2004)

46. Borchard G, Lueßen HL, De Boer AG, Verhoef JC, Lehr CM And Junginger H E. The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. Iii: effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro j. Control. Release 39, 131– 8(1996).

47. Kotz’e AF, Lueßen HL, De Leeuw BJ, De Boer (A)BG, Verhoef JC And Junginger HE . Comparison of the effect of different chitosan salts and n-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (caco-2) j. Control. Release 51, 35– 46(1998).

48. Lamprecht A, Koenig P, Ubrich N, Maincent P And Neumann D. Low molecular weight heparin nanoparticles: mucoadhesion and behaviour in caco-2 cells nanotechnology 17, 3673– 80(2006).

49. Ramadas M, Paul W, Dileep KJ, Anitha Y And Sharma CP. Lipoinsulin encapsulated alginate-chitosan capsules: intestinal delivery in diabetic rats j. Microencapsul 17, 405– 11 (2000).

50. Agnihotri SA, Mallikarjuna NN and Aminabhavi TM. Recent advances on chitosan-based micro-and nanoparticles in drug delivery J. Control. Release 100, 5– 28(2004).

51. Gerardo P. Carino, Edith Mathiowitz. Oral insulin delivery; Advanced Drug Delivery Reviews 35,249–257(1999).

52. Hanazaki K, Nose Y, Brunicardi FC. Artificial endocrine pancreas. J Am Coll Surg [electronic resource] [accessed 2006 Jan 20]. Available from: URL: http://www.sciencedirect.com/science?_ob=Article

53. Freitas RA. Current status of nanomedicine and medical nanorobotics [electronic resource] [accessed 2006 Jan 20]. Available from:url:http://www.nanomedicine.com/papers /nmrevmar05.pdf

54. Freitas RA. The future of nanofabrication and molecular scale devices in nanomedicine. [Electronic resource] [Accessed 2006 Jan 20]. Available from: URL: http://www.rfreitas.com/nano/futurenanofabnmed.htm.

55. Insulin nanopump for accurate drug delivery. [Electronic resource] [Accessed 2008 Aug 15]. Available from: http://thefutureofthings.com/news/1286/insulin-nanopump-for-accuratedrug- delivery.html

56. Èeka Nas Du’i, Kvalitetniji I Jednostavniji ‘Ivot. Medicinar [electronic resource] 2003 dec [accessed 2005 Feb 6]. Available from: URL: Http://medicinar.mef.hr/te kstovi.php?id=39

57. Stem Cells doi:10.1634/stemcells.2005-0367, published online March 23, 2006.

58. Yoshida S et al., Human cord blood-derived cells generate insulin producing cells in vivo, Stem Cells 23, 1409-1416, October 2005.

59. Sapir et al., Cell-replacement therapy for diabetes: generating functional insulin-producing tissue from adult human liver cells, PNAS 102, 7964-7969, 17 May 2005

60. Oh S H, et al., Adult bone marrow-derived cells trans-differentiating into insulin-producing cells for the treatment of type I diabetes, Lab Invest 84, 607-617, May 2004.

61. Fujikawa T et al, American Journal of Pathology 166, 1781-1791, June 2005.

62. Weissberg-benchell j, antisdel lomaglio j, seshadri r. Insulin pump therapy: a meta-analysis. Diabetes care. 2003; 26(4):1079-87.

63. Rudolf jw, hirsch ib. Assessment of therapy with continuous subcutaneous insulin infusion in an academic diabetes clinic. Endocrine practice. 2002; 8:401-5.

64. Bode BW, Sabbah HT, Gross TM, et al. Diabetes management in the new millenium using insulin pump therapy. Diabetes metab res rev. 2002; 18(suppl 1):s14-20.

65. Linkeshova R, Raoul M, Bott U, et al. Less severe hypoglycameia, better metabolic control, and improved quality of life in type 1 diabetes mellitus with continuous subcutaneous insulin infusion (csii) therapy; an observational study of 100 consecutive patients followed for a mean of 2 years. Diabetes med. 2002; 19(9):746-51.

66. Weissberg-Benchell J, Antisdel Lomaglio J, Seshadri R. Insulin pump therapy: a meta-analysis. Diabetes care. 2003; 26(4):1079-87.

67. Boland EA, Grey M, Oesterle A, et al. Continuous subcutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes.

68. Chantelau E, Spraul M, Muhlhauser I, et al. Long-term safety, efficacy and side effects of continuous subcutaneous insulin infusion treatment for type 1 (insulin dependent) diabetes mellitus: a one centre experience. Diabetologia. 1989; 32(7):421-6.

69. Diabetes control and complications trial research group: lifetime benefits and costs of intensive therapy as practiced in the dcct. Jama, 1996; 276:1409-1415

70. Bode BW, Steed RD, and Davidson PD: reduction in severe hypoglycemia with long-term continuous subcutaneous insulin infusion in type 1 diabetes. Diabetes care, 1996; 19:324-327.

Received on 25.12.2009

Accepted on 03.02.2010

Research J. Pharmacology and Pharmacodynamics 2(1): Jan. –Feb. 2010: 12-22