Coeliac Disease


Sometimes you may feel bloating and gals in the abdomen, diarrhoea after eaten wheat, barley or rye. Those symptoms may be due to something wrong in your digestive system. Let’s look at around what is happening and why those symptoms are occurring.

Coeliac disease sometimes called coeliac sprue or gluten-sensitive enteropathy. This disease is due to an immune reaction to eating gluten. Gluten is a protein found in wheat, barley and rye.


HLA DQ2 in 95%, the rest are DQ8, Autoimmune disease, Dermatitis herpetiformis.


The prevalence is 1 in 100-300 persons( Commoner if Irish). Can occurs in any age group, but peak in childhood and 50-60 years of age. Male to female ratio is 1:1, relative risk in first degree relatives is having six (6) fold.


Coeliac disease is immune mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It is a unique autoimmune disorder with environmental trigger by gluten and the auto-antigen (tissue Transglutaminase)


The signs and symptoms are different between children and adults. Adult may present with, diarrhoea, fatigue, weight loss, abdominal pain, bloating and gas, nausea and vomiting, constipation.

Some patients have sings and symptoms unrelated to the digestive system. Those includes,

  • Anaemia, usually due to iron deficiency.
  • Osteoporosis (loss of bone density), Osteomalacia (softening of bone).
  • Mouth ulcers.
  • Headaches and fatigue.
  • Joint pain.
  • Feeling of numbness and tingling sensation in the feet and hands.

Children who is having coeliac disease are having following digestive symptoms,

  • Nausea and vomiting
  • Chronic diarrhoea
  • Swollen belly
  • Constipation
  • Pale, foul smelling stools

Children will present with symptoms and signs relating to the inability to absorb nutrients.

  • Weight loss
  • Anaemia
  • Irritability
  • Short stature
  • Delayed puberty
  • Failure to thrive in infants
  • Damage to the enamel

Diagnosis of Coeliac Disease

The diagnosis of coeliac disease is done by clinical features with the support of serological and histological features. Antibodies; anti: transglutaminase is single preferred test.

Serology has high estimation sensitivity in the most studies. Biopsy is only seropositive. Negative serology should not necessarily reassure the clinician. The biopsy is done while taking gluten containing diet.

Marsh I or infiltrative lesion

These are nonspecific. It is known as lymphocyte enteritis. Patients occasionally present with positive serology. This is the common presentation in latent Coeliac disease. It is often missed by pathologist.

Marsh II Hyperplastic lesion

This is very common form of IBS. Could present with symptoms.

Marsh IIIa or Partial Villous Atrophy ( Destructive)

This is a form of complex and prevalent variety of subgroups, easily missed. Negative in Serology 60% – 70% of the patients. It is very common presentation in First degree relatives. Patients with 20 % first degree relatives had Coeliac disease.

Marsh IIIb or Subtotal Villous Atrophy

This is less common and easier to recognise. About 70% of the patient presents with positive serology. This is very close to the classical presentation.

Marsh IIIc or Total Villous Atrophy

This is classical coeliac disease. Serology is positive in almost 100% if not IgA- deficient.

Seropositive with normal histology

Atypical localisation in Terminal ileum. False positive results will given in Liver diseases and Autoimmune diseases.


Endoscopy should be done for entire small bowels. Normal duodenal biopsy do not exclude diagnosis. Segmental biopsy would be required.

Dermatitis herpetiformis

Gluten intolerance can cause itchy, blistering skin disease. This rash usually occurs on the elbows, knees, torso, scalp and buttocks. This condition is often associated with changes to the lining of the small intestine identical to those of celiac disease, but the skin condition might not cause digestive symptoms.

These patients can be treated with gluten- free diet or medication or both, to control the rash.


These patients can be recommended lifelong gluten free diet. Rice, Maize, soya, potatoes and sugar are ok. Limited consumption of Oats (<50g/dl), may be tolerated in patients with mild disease. Gluten- free biscuits, flour, bread and pasta are recommended. We can monitor the response by symptoms and by repeating serology.


  • Because of poor nutrition, they can develop anaemia.
  • Dermatitis herpetiformis.
  • Osteopenia and Osteoporosis.
  • Hyposplenism.
  • T cell lymphoma.
  • There is a high risk of malignancy, such as lymphoma, gastric, oesophageal and colorectal.
  • Neuropathies.

Diabetes Mellitus – Sings and Symptoms, Diagnosis and Treatment

Diabetes mellitus comprises a group of common metabolic disorders with related to hyperglycaemia. There are several types of Diabetes mellitus. Several factors contribute for diabetes mellitus including genetic factors, environmental factors. Depending of the aetiology of the DM factors contributing to hyperglycaemia include reduced insulin secretion, increased insulin resistant, decreased glucose utilisation, and increased glucose production. Due to the increased blood glucose levels the and metabolic dysregulation it causes pathophysiologic changes in multiple organ system. 

The current WHO diagnostic criteria for diabetes should be maintained

Fasting Plasma Glucose ≥ 7.0mmol/l (126mg/dl) or 2–h plasma glucose≥ 11.1mmol/l (200mg/dl). 

Classification of Diabetes Mellitus

Type 1 Diabetes Mellitus

The Type 1 diabetes mellitus is an autoimmune disorder in which the insulin-producing β cells of the pancrease are destroyed. Patients are dependent upon insulin therapy and prone to develop ketosis. The identical twin of a patient with type 1 diabetes has a 30-50% chance of developing the disease, implying that both genetic and environmental factors are involved. Two chromosome regions have been established as being associated with, and linked to, IDDM : the major histocompatibility complex (MHC) class II region and the insulin gene region (IDDM2;11p15).

Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is the commoner form, accounting for 90% of patients with diabetes, and affecting 5% of the world’s population. Type 2 diabetes mellitus is a heterogenous group of disorders characterized by variable degrees of insulin resistance, impaired insulin secretion, and ecsessive hepatic glucose production. Patients are typically obese adults. Insensitivity of the tissue to insulin (Insulin resistant) and inadequate pancreatic β cell response to blood glucose are characteristic, leading to overproduction of glucose by the liver and underutilization by the tissues. Ketosis is unusual as patients have sufficient insulin to prevent lipolysis. Although initially controlled with diet and oral hypoglycaemic, many patients eventually need supplemental insulin, making them insulin-requiring type 2 diabetes mellitus.

Other Specific types of Diabetes Mellitus

Other specific types of diabetes mellitus caused by,

  • Genetic defects [Maturity Onset Diabetes of Young (MODY) and other rare monogenic disorders]
  • Diseases of the exocrine pancreas – chronic pancreatitis, cystic fibrosis, hemochromatosis.
  • Endocrinopaties – acromegaly, Cushing’s syndrome, glucagonoma, pheochromocytoma, hyperthyroidism.
  • Drugs – nicotinic acid, glucocorticoids, thiazides, protease inhibitors.
  • Pregnancy – Gestational DM

The phenotype of these monogenetic and secondary types of DM typically resembles type 2 DM. The severity of type 2 DM depends of the degree of beta cell dysfunction and prevaling insulin resistance. Type 1 DM usually results from autoimmune destruction of pancreatic beta cells, It’s also known as juvenile-onset diabetes because its peak incidence is in children and adolescents.

Prevalence of Diabetes Mellitus

The number of people with diabetes has risen from 108 million in 1980 to 422 million in 2014. The global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014. Diabetes prevalence has been rising more rapidly in middle- and low-income countries. Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation. In 2016, an estimated 1.6 million deaths were directly caused by diabetes. Another 2.2 million deaths were attributable to high blood glucose in 2012. Almost half of all deaths attributable to high blood glucose occur before the age of 70 years. WHO estimates that diabetes was the seventh leading cause of death in 2016. Healthy diet, regular physical activity, maintaining a normal body weight and avoiding tobacco use are ways to prevent or delay the onset of type 2 diabetes.

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Diagnosis of Diabetes Mellitus

For the diagnosis of diabetes mellitus your doctor will order you to do your blood tests. There are criteria for the diagnosis of DM.

  • Fasting plasma glucose ≥ 7.0 mmol/L (≥ 126 mg/dL)
  • Symptoms of diabetes plus a random blood glucose conce
  • ntration ≥ 11.1 mmol/L (≥ 200 mg/dL)
  • 2-hour plasma glucose ≥ 11.1 mmol/L (200 mg/dL) during a 75 g oral glucose tolerance test.
  • Hemoglobin A1c > 6.5%

Two intermediate categories also have been designated.

  • Impaired fasting glucose ( IFG) for a fasting plasma glucose level of 5.6-6.9 mmol/L or 100-125 mg/dL.
  • Impaired glucose tolerance test (IGT) for plasma glucose level of 7.8 – 11.1 mmol/L or 140-199 mg/dL of 2 hours after a 75 g of oral glucose load.

Those patients who had IFG values and IGT values do no have Diabetes mellitus, but they have high risk of developing diabetes mellitus and cardiovascular diseases in future.

Metabolic Syndrome

The metabolic syndrome also called as insulin resistance syndrome or syndrome X is a commonly used term to describe the derangements that includes insulin resistance, hypertension, dyslipidemia, central or visceral obesity, and endothelial dysfunction. This is associates with accelerated cardiovascular disease. Individuals with metabolic syndrome present with or without diabetes mellitus.

Complications of Diabetes Mellitus

Long term complications occur in all forms of diabetes. Good glycaemic controls has been shown conclusively to prevent or ameliorate diabetic microvascular complications.

Microvascular Complications

Vascular complications account for 75% of deaths. The incidence of coronary artery occlusion is five times higher in diabetes than non-diabetics, leading to claudication, rest pain, ulcer formation and gangrene.

Small vessel disease ( diabetic microangiopathy) is associated with homogenous thickening of vascular basement membrane. It produces renal failure, associated with retinopathy. It also associated with formation of gangrene of the skin and feet with wedge-shaped infarcts.

Small vessel disease ( diabetic microangiopathy) is associated with homogenous thickening of vascular basement membrane. It produces renal failure, associated with retinopathy. It also associated with formation of gangrene of the skin and feet with wedge-shaped infarcts.

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Eye Complications

Diabetes mellitus directly associated with development of eye complications. Fifty percent of patients have background retinopathy after 10 years of diabetes.

  • Microaneurysms are focal dilatation of capillary walls, not visible with the ophthalmoscope.
  • Dot or blot intraretinal haemorrhages.
  • Soft ( cotton-wool) exudates due to micro infarction of superficial nerve fibres.
  • Hard exudates due to leakage of plasma into the retina.
  • Retinal oedema.
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In proliferative retinopathy new vessels proliferate in response to ischaemia, mainly near the disc margins. These fragile vessels are prone to haemorrhage in to the retina and virtuous. Vitreous haemorrhage is followed by fibrosis and contraction leading to retinal ditachment and thrombotic glaucoma. Laser photocoagulation destroys new vessels and reduces oxygen requirements throughout the retina, thereby retarding new vessel proliferation.


Thirty percent of patients with type I diabetes develop end -stage renal failure. Hyperfiltration and increased creatinine clearance occur early after the onset of diabetes.

After several years microvascular changes (basement membrane thickening, hyaline degeneration of afferent and efferent arterioles) are associated with increased glomerular permeability and proteinuria. Kimmelstiel-Wilson nodules (nodular glomerulosclerosis) are pathognomonic of diabetic nephropathy.

Present of microalbuminuria indicates the onset of diabetic renal disease. Normal 24 hour urinary albumin excretion is less than 15 mg. Microalbuminuria is defined as a 24 hour urinary albumin excretion of 30-300mg. Once persistent proteinuria occurs (>300mg in 24h), renal failure usually develops within 5 years.

The progression of microalbuminuria is closely associates with changes in blood pressure, and control of blood pressure may be more important than glycaemic control in preventing renal disease.

Angiotensin-converting enzyme inhibitors prevent progression of microalbuminuria to proteinuria in non-hypertensive patients with IDDM. Pyelonephritis is commoner in diabetics, Renal papillary necrosis can occur as a result of ischaemia of the papillae, which may slog and cause obstruction.

Neuromuscular complications

Neuromuscular complications affect up to 50% of patients with long-standing diabetes.

Peripheral neuropathy is the commonest, initially causing loss of ankle jerks and absent vibration sense in the lower limbs. Later there is loss of touch and pain sensation. Patients often complain of numbness, and a burning sensation that is worse at night. Chronic painless ulcers develop in areas of repeated trauma ( eg. pressure points with ill-fitting footwear). Painless neuropathic arthropathy ( Charcot’s joints) most commonly affects the tarsometatarsal joints.

Mononeuritis is thought to results from schema following occlusion of a vasa nervorum. The third cranial nerve, ulnar nerve or lateral popliteal nerve are most commonly affected. More than one nerve can involved. They are often transient, and spontaneous recovery of function usually over a period of months.

Diabetic amyotrophy usually occurs in middle aged diabetes who develop painful, asymmetrical weakness and wasting of the quadriceps muscles. Improving diabetic control is often associated with recovery.

Autonomic neuropathy produces impotence, nocternal diarrhoea, gastroparesis, postural hypotension and hypotonic bladder.


Insulin sensitivity may occur in the first month of insulin therapy with production of tender lumps after each injection. Spontaneous recovery occurs, and no change of therapy is indicated.

Lipodystrophy is painless atrophy or hypertrophy at injection sites. It is uncommon since the introduction of recombinant human insulins.

Necrobiosis lipoidica diabeticorum is rare but pathognomonic of diabetes and may precede it. It is characteriszd by atrophy of subcutaneous collagen, usually over the shins. The lesions are violet rings with yellow masses at the periphery and scarring and atrophy at the centre.

Intercurrent infection

Intercurrent infection is common in diabetics, particularly of the urinary tract and skin. Tuberculosis and candidiasis (vulvitis and balanitis) are more common in diabetes.

Cardiovascular complications

Coronary artery disease, congestive heart failure, peripheral vascular disease, Stroke.

Neurologic Complications

Distal symmetric polyneuropathy, polyradiculopathy, mononeuropathy, autonomic neuropathy.

Lower extremity

Foot deformity (hammer toe, claw toe, Charcot foot), Foot ulceration, Amputation.

Dermatological Complications

Infections ( folliculitis, furunculosis, cellulitis), necrobiosis, poor healing, ulcers, gangrene.

Clinical Features of Diabetes Mellitus

Common presenting symptoms of DM include,

  • Polyuria
  • Polydipsia
  • Weight loss
  • Fatigue
  • Weakness
  • Blurred vision
  • Frequent superficial infections
  • Poor wound healing

Taking history of a patient with DM and Examination

Late diagnosis is due to lack of symptoms. When taking the history it should be complete medical history with weight, Exercise, smoking, alcohol use, family history of DM, and any risk factors for cardiovascular disease. Some patients are coming with known diabetes mellitus. When taking history from them it is important assess the prior diabetic care, HbA1c levels, Self monitoring blood glucose results, frequency of hypoglycaemia, and patient knowledge about DM.

When doing physical examination of the patients with DM, special attention should be given to retinal examination, measuring orthostatic blood pressure, foot examination including vibratory sensation and monofilament testing), peripheral pulses, and check insulin injection sites.

Criteria for testing for pre-diabetes and diabetes in asymptomatic individuals

  • First degree relative with diabetes
  • Physical inactivity
  • Previously identified IFG,IGT, or haemoglobin A1c of 5.7-6.4%
  • History of GDM or delevery of baby > 4kg
  • Hypertension ( Blood pressure > 140/90 mmHg)
  • HDL cholesterol level ≤ 0.90 mol/L (35mg/dL) and/or a triglyceride level ≥ 2.82 mmol/L(250mg/dL)
  • Polycystic ovary syndrome or acanthosis nigricans
  • History of vascular disease

Management of Diabetes Mellitus

The aims of management of diabetes mellitus are to improve symptoms of hyperglycaemia and minimise the risks of long-term microvascular and macro-vascular complications.

Treatment methods of diabetes mellitus are,

  • Dietary / lifestyle modification.
  • Oral- anti-diabetic drugs
  • Injected therapies

In patients with suspected type 1 diabetes mellitus, urgent treatment with insulin is required and prompt referral to a specialist is usually needed.

In patients with suspected type 2 diabetes, first line therapy includes advices about dietary and lifestyle modification. Those patients who do not achieve glycemic target is required oral anti diabetic drugs. At the same time oral anti diabetic drugs need to be started for the patients who present with hyperglycaemia symptoms and with high HbA1c.

In parallel with hyperglycaemia, other risk factors for complications of diabetes should be addressed. Those includes hypertension and dyslipidaemia. Patients who are smokers should be advised for smoke cessation.

Adequate glycaemic control can be obtained by diet and lifestyle modification alone in approximately 50% of patients. Oral anti diabetic medication is required for 20-30% of patients and 20-30% of patients require insulin.

Management goals of diabetes

  • Allow the patient to lead a completely normal life.
  • To remain not only symptom free but in good health.
  • To achieve a normal metabolic state.
  • To prevent from getting long term complications of diabetes.

Diet and Lifestyle

Good glycaemic control is achieved by lifestyle changes such as undertaking regular physical activity, having healthy diet, reducing alcohol consumption. Those good habits need to be sustained. Patients should be encouraged to stop smoking.

Diet control for diabetes

All patients with diabetes give their special attention for the diet. Nutritional advice should be tailored to individual and need to consider for their lifestyle and age.


Both the amount and source of carbohydrate determines post-prandial glucose. The glycaemic index of a carbohydrate-containing food is a measure of the change in blood glucose following its ingestion relative to the rise in blood glucose observed following a liquid oral glucose tolerance test. Consumption of foods with low glycaemic index in encouraged because they produce slow, gradual rise in blood glucose.

Examples of starchy foods which have low glycaemic index such as basmati rice, spaghetti, porridge, noodles, granary breads, and beans and lentils. In addition method of food preparation and food processing can influence the Glycaemic index of foods. Glycaemic index is useful in choosing between the type of carbohydrate, it does not address the total amount consumed.

Fat consumption in diabetes

The intake of total fat should be restricted to less than 35% of energy intake, with less than 10% as saturated fat, and 10-20% from monounsaturated fat through consumption of oils and spreads made from olive, rapeseed or groundnut oils.

Salt consumption in diabetes

Salt should be restricted to daily consumption no more than 6g daily.

Weight management in diabetes

Most people with type 2 diabetes are obese. So its very important to manage the weight of patients with diabetes. Many anti diabetic drugs including insulin encourage weight gain. Obesity with increased waist circumference predicts insulin resistance and cardiovascular risk. Weight gain is a balance of the energy consumption and daily energy expenditure. Weight loss can be achieved through a reduction in energy intake and an increased in energy expenditure. Most recent studied shows bariatric surgery has been shown to induce marked weight loss on obese patients with type 2 diabetes and it is often associated with significant improvements in HbA1c and withdrawal of or reduction in diabetes medication.

Exercise in diabetes

Al patients with diabetes should be advised to engage in physical activity and to maintain this in the long term. This activities can include walking, cycling, gardening, swimming. It is advised to engage I a weekly minimum of 2.5 hours of moderate-intensity exercise or 75 minutes of vigorous-intensity exercise or combination of both. The aerobic (moderate-intensity) activity should be performed for at least 10 minutes each time and spread throughout the week, with at least 30 minutes on at least 5 days of the week. This is also recommended for older adults far as their abilities allow. If you can combine both aerobic and resistance exercise may lead to greater improvements in glycaemic control.

In type 1 diabetes, doing exercise can increase the risk of getting hypoglycaemia. Patients are advised to take specialist advice on taking extra carbohydrate, reducing insulin doses and choosing an injection site.

Alcohol consumption in diabetes

Alcohol is recognised as both beneficial and harmful effects on cardiovascular disease. In UK the weekly recommended consumption of alcohol intake is 14U for woman and 21U for men. Alcohol will reduce hypoglycaemia awareness and increase hypoglycaemia risk. Alcohol has high calorie content and patients with diabetes are advised regarding the implication of weight management, which can be altered when consume alcohol.

Drug Management in Diabetes

Several drugs are used to reduce hyperglycaemia, in the past only few drugs for the management of diabetes were available, but with the time now fortunately there are several new types of drugs which can be used for the management of diabetes. The biguanide metformin and the sulphonylureas and insulins were available for so many years. Acarbose also used to reduce hyperglycaemia. The never drugs include thiazolidinediones, dipeptidyle peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, sodium and glucose transporter 2 (SGLT2) inhibitors. The older drugs are cheaper and they reduce the microvascular complications. So its advised to use older drugs as the first line therapy. There are no enough researched to confirm whether newer drugs reduce microvascular complications. So first line drugs such as Metformin, Tolbutamide are used initially and the newer drugs are added if there is poor control of hyperglycaemia with them.


Metformin is the only biguanide available now. It is widely used as first line therapy for type 2 diabetes, irrespective of the body weight. For obese patients with the type 1 diabetes, Metformin is given as adjunct to insulin therapy. Metformin has gastrointestinal side effects such as abdominal cramps, diarrhoea, bloating and nausea, around 25% of patients will get these side effects. About 5% of patients are unable to tolerate metformin even if very low doses.

Metformin is an insulin sensitiser, because it lowers insulin levels. Its main effects are on fasting glucose. Metformin reduces hepatic glucose production, also increase insulin mediated glucose uptake, has effects on gut glucose uptake and utilisation.

Metformin does not cause hypoglycaemia and has established benefits in microvascular disease. It is used in all patients with type 2 diabetes as first line treatment. When starting metformin initially it iOS started as a low dose as 500mg twice daily. It will minimise the gastrointestinal side effects. The usual maintenance dose is 1g twice daily. There is a modified release form of metformin which may be better tolerated with gastrointestinal side effects.

Metformin should be use with precautions in patients with renal impairment. Because metformin is cleared by the kidneys, it will accumulate in renal impairment. So the dose of metformin should be halved when estimated glomerular filtration rate (eGFR) is 30-45 mL/min, and it should not use in patients below an (eGFR) of 30mL/min.

Metformin can cause lactic acidosis. It’s use is also contraindicated in patients with impaired hepatic function and those who drink alcohol in excess, where the risk of getting lactic acidosis is significantly high. In some serious medical conditions it should be discontinued temporary such as severe shock and hypoxia. In such circumstances substitution with insulin is recommended.


Sulphonylureas promote pancreatic β-cell insulin secretion. Similar to metformin, the long term benefits of sulphonylurea in lowering the microvascular complications.

Sulphonyleurea acts by closing the pancreatic β-cell ATP-sensitive potassium channel, decreasing K+ efflux, which ultimately triggers insulin secretion. Megalitinides, (eg: repaglinide and nateglinide) also work in this way. Sulphonylureas are add-on to metformin, if glycaemia is inadequately controlled on metformin alone. There is a high risk of developing hypoglycaemia with use of sulphonylurea. Because the closure of ATP sensitive K channels brings up unregulated insulin secretion. There are number of sulphonyleurea used such as gliclazide and glibenclamide. Glibenclamide is long acting and more prone to develop hypoglycaemia. So it’s better to avoid glibenclamide in elderly patients. Other sulphonyleurea include glimepiride and glipizide. The dose response of all sulphonyleureas is steepest at low doses; little additional benefit is obtained when the dose is increased to maximal levels.

Alpha-glucosidase inhibitors

Acarbose and miglitol are available and are taken with each meal. They delay carbohydrate absorption in the gut by inhibiting disaccharidases. Both moderately increase glycaemic control by lowering post prandial blood glucose level. These drugs can be combined with sulphonylureas. There are several GI side effects such as flatulence, abdominal bloating and diarrhoea.


These drugs were widely used earlier, but their usage has declined due to some side effects. Rosiglitazone, increases the risk of myocardial infarction. The other drug pioglitazone does not increase the risk of myocardial infarction, but it exacerbate here failure by causing fluid retention. Pioglitazone is very effective in lowering blood glucose level and appears most effective in insulin resistant patients. It has a beneficial effect on reducing fatty liver. It can be given with insulin therapy, but due to the effect of fluid retention it must be given with precautions.

These drug bind and activate peroxisome proliferator activated receptor – γ , a nuclear receptor in adipose tissue. TZDs enhances the actions of endogenous insulin. TZDs does not increases plasma insulin concentration and it will not result in developing hypoglycaemia. TZDs can cause increase fat mass and body weight due to the increase of pre-adipocyte differentiation.

Recent studies shows increase the risk of bone fracture and possibility of developing bladder cancer. Because of these serious side effects, use of pioglitazone has reduced dramatically.

SGLT 2 Inhibitors

Glucose is filtered freely in the renal glomeruli and reabsorbed in the proximal tubules. The Sodium and Glucose transporter 2 (SGLT2) involves in the reabsorption in glucose. Inhibition of SGLT 2 receptors results in 25% reduction in the reabsorption of glucose from renal proximal tubules. A new drug of dapagliflozin was licensed recently. There is reduction of blood glucose level and calorie loss with subsequent weight loss. But due to glycosurea there is more susceptibility to develop recurrent urinary tract infections and genital fungal infections.

Incretin-based therapies: DPP-4 inhibitors and GLP-1 analogues

When glucose load is given by orally, there is increase in insulin secretion. This is called incretin effect. It reflects the release of incretin peptide from the gut. The incretin hormones are primarily glucagon like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). These are rapidly broken down by peptidase DPP-4 (dipeptidyle peptidase 4).The incretin effect is diminished in type 2 diabetes, it is based for the development of therapeutic approaches. The ‘glistens’, or DPP-4 inhibitors, prevent breakdown and therefore enhance the concentrations of endogenous GLP-1 and GIP. The first drug which was released to the market is sitagliptin; others now available in the market are vildagliptin, saxagliptin and linagliptin.

There are some products of injectable GLP1 analogues, which lower blood glucose and reduce weigh. Currently available GLP-1 receptor agonist include, exenatide which is given twice daily, exenatide MR which is given once weekly, and liraglutide given once daily.

Both incretin based therapies only promote insulin secretion when there is a glucose trigger for insulin secretion. So when a state of normal blood glucose level, the insulin secretion is not augmented and these agents do not causing hypoglycaemia.

Insulin therapy for diabetes

Insulin was first discovered in 1921 and used for the management of type 1 diabetes. Initially insulin was prepared by the extraction and purification from pancreata of cows and pigs. Now the recombinant DNA technology enabled large-scale production of human insulin. More recently the amino acid sequence of insulin has been altered to produce analogues of insulin. These analogues are different form the rate of absorption from the site of injection. By addition of protamine and zinc ions to the short acting soluble insulin at neutral pH it can convert to isophane insulin or with addition of excess zinc ions it can convert to lente insulin. There are pre-mixed preparations with which contain short acting and isophane insulin in various proportions. Usually in most countries the concentration of insulin in one vial has been standardised to 100U/mL.

Insulin is injected subcutaneously into the anterior abdominal wall, upper arms, outer thighs and buttocks. The rate of absorption of insulin depends on several factors. Those factors are insulin formation, injection site, volume of the injection, local massage, depth of the injection, skin temperature. When injecting insulin, repeated administration to the same site should be avoided to prevent from getting lipodystrophy. The rate of absorption of insulin is reduced if injected to areas where lipodystrophy present.

Once injected, insulin in blood has s short half life of just a few minutes. Insulin is removed mainly by the liver and kidneys. In patients with renal failure and liver diseases, the insulin concentration is elevated.

There are several methods which can use for injection of insulin. Insulin can be injected by using a fine needle and a plastic syringe. This can be repeated for the same person. The other method is the injection of insulin by using a pen injectors containing insulin in cartridges. The cartridge contains sufficient amount of insulin for multiple dosages.

Insulin analogues are using nowadays. Soluble insulin should be injected 30 minutes before eating. But rapid acting insulin is injected just before the meals of during the meals or just after the meals. Long acting insulin administered once daily as they maintain basal insulin level for 24 hours. The adverse effects are minor with insulin analogues.

Adverse effects of insulin therapy in diabetes

Hypoglycaemia and weight gain occur with insulin usage. Some patients can develop peripheral oedema. Some patients develop insulin antibodies. Local allergy and lipohypertrophy or lipoatrophy can develop at injection sites.

Insulin dosing and regimens in diabetes

Several factors consider when selecting insulin regimen. It depends on the desired level of glycaemic control, the severity of underlying insulin deficiency, the patients lifestyle, his or her ability to adjust the insulin dose. Usually most of type 1 diabetes patients require toes or more injections of insulin daily. In patients with type 2 diabetes, insulin is injected as a once a daily long acting insulin. This administration is given either as a combination with oral hypoglycaemic drugs or insulin alone. In some patients more frequent insulin injections are required to control hyperglycaemia.

The usual initial insulin administration is twice daily dose with short acting insulin and intermediate acting insulin. It is usually given in combination before breakfast and the evening meal. Initially, two thirds of the total daily requirement of insulin is given in the morning in a ratio of short-acting to intermediate-acting of 1:2, and the remaining third is given in the evening. Pre-mixed preparations are available containing different proportions of soluble insulin and isophane insulins. (eg; 30:70 and 50;50). It is advised to shake the vial before using to resuspended it before administration.

Multiple injection regimens are popular, with short acting insulin being taken before each meal and intermediate or long acting insulin being injected once or twice daily. This is c called intensive insulin therapy. This gives greater freedom with regard to meal timing and more variable day to day physical activity.

Other ways of insulin therapy for management of diabetes

A battery powered portable pumps can provide continuous subcutaneous (CSII), or intraperitoneal or intravenous infusion of insulin without reference to the blood glucose level. The rate of insulin infusion can be adjusted.

Whole pancreas transplantation

The whole pancreas transplantation is done for several patients. Long term immunosuppression is needed for those patients. At present this is done for the patients with en stage renal failure who requires combined kidney and pancreas transplant.

Some centres, transplant of isolated pancreatic cells are carried out. Researches are doing to develop methods to induce tolerance to islets and the potential use of stem cells as a long term treatment plan.


Davidson’s Principles and Practice of Medicine/ 22nd Edition, Diabetes mellitus

Harrison’s Manual of Medicine/18th Edition, Diabetes Mellitus