Diabetes Mellitus

By Dr. Khalid S. R. Khan

Diabetes =passing through

excessive amount of urine produced by sufurer

Mellitus= pertaining to honey

Diabetes mellitus (DM)

 Diabetes mellitus (DM) is a chronic metabolic disorder characterized by hyperglycemia and glycosuria It is a multisystem disease with both biochemical & anatomical/structural consequences It is a chronic disease of carbohydrate, fat, and protein metabolism caused by the lack of insulin, It results from the marked and progressive inability of the pancreas to secrete insulin.

Classification
Diabetes can be grouped into 4 major categories
 Type 1 (IDDM) Absolute deficiency of insulin resulting from -cell destruction Type 2 (NIDDM) progressive insulin secretary defect in the back ground of resistance to action of insulin by target organs and tissues

Secondary causes such as drugs (steroids), genetics (down syndrome) Gestational DM

Diabetes Mellitus
 Type 1 Diabetes  Type 2 Diabetes

- cells that produce insulin are destroyed - results in insulin dependence - commonly detected before 30

- blood glucose levels rise due to 1) Lack of insulin production 2) Insufficient insulin action (resistant cells) - commonly detected after 40 - effects > 90% - eventually leads to -cell failure
(resulting in insulin dependence)

Gestational Diabetes
3-5% of pregnant women develop gestational diabetes

 Type 1 diabetes mellitus has wide geographic variation in incidence and prevalence.  Annual incidence varies from 1-3 cases per 100,000 population in China, to 41.4 cases per 100,000 population in Finland.  Substantial variations are observed between nearby countries with differing lifestyles, such as Estonia and Finland, and between genetically similar populations, such as those in Iceland and Norway.

Indian data suggest an incidence of 10.5/100,000/year India would have 79 million diabetics by 2030 Most countries report that incidence rates have at least doubled or more in the last 20 years. Incidence appears to increase with distance from the equator.

Type 1-Diabetes mellitus 1 Insulin is produced by the beta cells of the islets of Langerhans located in the pancreas, and the absence, destruction, or other loss of these cells destruction, results in type 1 diabetes (insulin-dependent (insulindiabetes mellitus [IDDM]).  Most children with diabetes have type 1 diabetes mellitus (T1DM) and a lifetime dependence on exogenous insulin.

Type 2-Diabetes mellitus 2Type 2 diabetes mellitus [NIDDM] is a [NIDDM] heterogeneous disorder. Most patients with type 2 diabetes mellitus have insulin resistance, and their beta cells lack the ability to overcome this resistance.

Type 2-Diabetes mellitus 2 This form of diabetes was previously uncommon in children,  In almost 20% or more of new patients with 20% diabetes in childhood & adolescence have type 2 diabetes mellitus,  A change associated with increased rates of obesity. obesity.  Other patients may have inherited disorders of insulin release, leading to maturity onset diabetes of the young (MODY) or congenital diabetes

MODY MODY is a monogenic form of diabetes with an autosomal dominant mode of inheritance:
Mutations in any one of several transcription factors or in the enzyme glucokinase lead to insufficient insulin release from pancreatic -cells, causing MODY. Different subtypes of MODY are identified based on the mutated gene.

` Originally, diagnosis of MODY was based on presence of non-ketotic hyperglycemia in adolescents or young adults in conjunction with a family history of diabetes.
 However, genetic testing has shown that MODY can occur at any age and that a family history of diabetes is not always obvious.

MODY-

MODY` Within MODY, the different subtypes can essentially be divided into 2 distinct groups: glucokinase MODY and transcription factor MODY, distinguished by characteristic phenotypic features and pattern on oral glucose tolerance testing. ` Glucokinase MODY requires no treatment, while transcription factor MODY (i.e. Hepatocyte nuclear factor -1alpha) requires low-dose sulfonylurea therapy and ` PNDM (caused by Kir6.2 mutation) requires high-dose sulfonylurea therapy.

Gestational diabetes
` A form of glucose intolerance that is diagnosed in some women during pregnancy. ` Gestational diabetes occurs more frequently among obese women and women with a family history of diabetes. ` During pregnancy, gestational diabetes requires treatment to normalize maternal blood glucose levels to avoid complications in the infant. ` After pregnancy, 5% to 10% of women with gestational diabetes are found to have type 2 diabetes. ` Women who have had gestational diabetes have a 20% to 50% chance of developing diabetes in the next 5-10 years.

Secondary causes of Diabetes mellitus include:

` ` ` ` ` ` `

Secondary DM

Acromegaly, Cushing syndrome, Thyrotoxicosis, Pheochromocytoma Chronic pancreatitis, Cancer Drug induced hyperglycemia:
Atypical Antipsychotics - Alter receptor binding characteristics, leading to increased insulin resistance. Beta-blockers - Inhibit insulin secretion. Calcium Channel Blockers - Inhibits secretion of insulin by interfering with cytosolic calcium release. Corticosteroids - Cause peripheral insulin resistance and gluconeogensis. Fluoroquinolones - Inhibits insulin secretion by blocking ATP sensitive potassium channels. Naicin - They cause increased insulin resistance due to increased free fatty acid mobilization. Phenothiazines - Inhibit insulin secretion. Protease Inhibitors - Inhibit the conversion of proinsulin to insulin. Thiazide Diuretics - Inhibit insulin secretion due to hypokalemia. They also cause increased insulin resistance due to increased free fatty acid mobilization.

` Prediabetes is a term used to distinguish people who are at increased risk of developing diabetes. People with prediabetes have impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). Some people may have both IFG and IGT. ` IFG is a condition in which the fasting blood sugar level is elevated (100 to 125 milligrams per decilitre or mg/dL) after mg/dL) an overnight fast but is not high enough to be classified as diabetes. ` IGT is a condition in which the blood sugar level is elevated (140 to 199 mg/dL after a 2-hour oral glucose tolerance mg/dL 2test), but is not high enough to be classified as diabetes.

Progression to diabetes among those with prediabetes is not inevitable. Studies suggest that weight loss and increased physical activity among people with prediabetes prevent or delay diabetes and may return blood glucose levels to normal. People with prediabetes are already at increased risk for other adverse health outcomes such as heart disease and stroke.

The etiology of type 1 DM has a strong genetic component. Nevertheless, identical twins have a concordance rate for type 1 DM of less than 50%. Most cases (95%) of type 1 diabetes mellitus are the result of environmental factors interacting with a genetically susceptible person.

Human leukocyte antigen (HLA) class II molecules DR3 and DR4 are associated strongly with type 1 diabetes mellitus. Patients expressing DR3 are also at risk for developing other autoimmune endocrinopathies and celiac disease. These patients are more likely to develop diabetes at a later age, to have positive islet cell antibodies, and to appear to have a longer period of residual islet cell function.

Potential triggers for immunologically mediated destruction of the beta cells include Viruses (eg, mumps, rubella, coxsackievirus B4), Toxic chemicals, Exposure to cow s milk in infancy, & Cytotoxins. After 80-90% of the beta cells are destroyed, hyperglycemia develops and diabetes may be diagnosed.

Chemical causes Streptozotocin and RH-787, a rat poison, selectively damage islet cells and can cause type 1 diabetes mellitus. Other causes Congenital absence of the pancreas or islet cells Pancreatectomy Type 1 diabetes mellitus secondary to pancreatic damage (ie, cystic fibrosis, chronic pancreatitis, thalassemia major, hemochromatosis, hemolyticuremic syndrome)

Pathophysiology
 Insulin is essential to process carbohydrates, fat, and protein.  Insulin reduces blood glucose levels by allowing glucose to enter muscle cells and by stimulating the conversion of glucose to glycogen (glycogenesis) as a carbohydrate store.

Pathophysiology
 Insulin also inhibits the release of stored glucose from liver glycogen (glycogenolysis) & slows the breakdown of fat to triglycerides, free fatty acids, & ketones.  It also stimulates fat storage.  Additionally, insulin inhibits the breakdown of protein & fat for glucose production (gluconeogenesis) in both liver & kidneys.

Pathophysiology
 Hyperglycemia (ie, random blood glucose concentration more than 200 mg/dL ) results when insulin deficiency leads to  Uninhibited gluconeogenesis & prevents the use & storage of circulating glucose.  The kidneys cannot reabsorb the excess glucose load, causing glycosuria, osmotic diuresis, thirst, and dehydration.

Pathophysiology
Increased fat & protein breakdown leads to ketone production & weight loss. Without insulin, a child with type 1 diabetes mellitus wastes away and eventually dies due to Diabetic KetoAcidosis (DKA).

Pathophysiology

The most easily recognized symptoms of type 1 diabetes mellitus (T1DM) are secondary to

Hyperglycemia, Glycosuria, and Diabetic ketoacidosis (DKA).

Hyperglycemia Hyperglycemia alone may not cause obvious symptoms, although some children report General malaise, Headache, and weakness. They may also appear irritable and become illtempered. The main symptoms of hyperglycemia are secondary to osmotic diuresis and glycosuria.

Glycosuria Leads to increased urinary frequency and volume (eg, polyuria), Which is particularly troublesome at night (eg. nocturia) and often leads to enuresis in a previously continent child. These symptoms are easy to overlook in infants because of their naturally high fluid intake and diaper/napkin use.

Polydipsia Increased thirst, which may be insatiable, is secondary to the osmotic diuresis causing dehydration.

Weight loss Insulin deficiency leads to uninhibited gluconeogenesis, causing breakdown of protein and fat. Weight loss may be dramatic, although the child's appetite usually remains good. Failure to thrive and wasting may be the first symptoms noted in an infant or toddler and may precede frank hyperglycemia.

Nonspecific malaise Although this condition may be present before symptoms of hyperglycemia, or as a separate symptom of hyperglycemia, it is often only retrospectively recognized.

Other nonspecific findings include the following:

Hyperglycemia impairs immunity and renders a child more susceptible to recurrent infection, particularly of the urinary tract, skin, and respiratory tract. Candidiasis may develop, especially in groin and flexural areas.

Symptoms of ketoacidosis These symptoms include the following: Severe dehydration Smell of ketones Acidotic breathing (ie, Kussmaul respiration), masquerading as respiratory distress Abdominal pain Vomiting Drowsiness and coma

WHO Criteria For Diagnosis of DM

Management of Diabetes Mellitus

 The major components of the treatment of diabetes are:

A B C

Diet and Exercise

Oral hypoglycaemic therapy

Insulin Therapy

`Diet is a basic part of management in every case. Treatment cannot be effective unless adequate attention is given to ensuring appropriate nutrition.

The aim of dietary management is To balance the child's food intake with insulin dose and activity & To keep blood glucose concentrations as close as possible to reference ranges, Avoiding extremes of hyperglycemia and hypoglycemia

Dietary management is an essential component of diabetes care. Diabetes is an energy metabolism disorder, and before insulin was discovered, children with diabetes could be kept alive by a diet severely restricted in carbohydrate and energy intake. These measures led to a long tradition of strict carbohydrate control and unbalanced diets. More recent dietary management of diabetes emphasizes a healthy, balanced diet, high in carbohydrates and fiber and low in fat.

The following are among the most recent consensus recommendations Carbohydrates should provide 50-55% of daily 50energy intake. Fat should provide 30-35% of daily energy intake. 30Protein should provide 10-15% of daily energy 10intake.

oView these recommendations in the patient's cultural context.

Type 1 diabetes mellitus requires no restrictions on activity; exercise has real benefits for a child with diabetes. Most children can adjust their insulin dosage and diet to cope with all forms of exercise. The current guidelines are increasingly sophisticated and allow children to compete at the highest levels in sport. sport.

B. Oral Anti-Diabetic Agents AntiThere are currently four classes of oral antidiabetic agents:
i. Biguanides ii. Insulin Secretagogues Sulphonylureas iii. Insulin Secretagogues Non-sulphonylureas iv. -glucosidase inhibitors v. Thiazolidinediones (TZDs)

` If glycaemic control is not achieved (HbA1c > 6.5% and/or; FPG > 7.0 mmol/L or; RPG >11.0mmol/L) with lifestyle modification within 1 3 months, ORAL ANTIDIABETIC AGENT should be initiated. ` In the presence of marked hyperglycaemia in newly diagnosed symptomatic type 2 diabetes (HbA1c > 8%, FPG > 11.1 mmol/L, or RPG > 14 mmol/L), oral antidiabetic agents can be considered at the outset together with lifestyle modification.

As first line therapy:

` Obese type 2 patients, consider use of metformin, acarbose or TZD. metformin, ` Non-obese type 2 patients, consider the use of metformin or insulin Nonsecretagogues ` Metformin is the drug of choice in overweight/obese patients. TZDs and acarbose are acceptable alternatives in those who are intolerant to metformin. metformin. ` If monotherapy fails, a combination of TZDs, acarbose and metformin is recommended. If targets are still not achieved, insulin secretagogues may be added

All children with type 1 diabetes mellitus (T1DM) require insulin therapy.

Insulin must be given parenterally, & this effectively means subcutaneous injection. All search for alternatives continues, including oral sprays, sublingual lozenges, and delayed-absorption delayedcapsules, But failed to generate sufficient benefits.

What is Insulin?

 Produced within the pancreas by F cells, islets of langerhans identified by Paul Langerhans in 1869
Islets of Langerhans 1 million islets
E cells secrete glucagons F cells produce insulin, most abundant H cells secrete somatostatin

It is very difficult for small proteins to fold into stable structures so larger precursors are synthesized first Stored as F granule When F cell is appropriately stimulated, insulin is secreted from the cell by exocytosis and diffuses into islet capillary blood

Glucose transported into F cell by a glucose transporter Results in membrane depolarization and an influx of extracellular calcium Fusion of insulin storage vesicle in plasma occurs Hexamer released from cell as crystal and dissolves to monomer
Reasons for monomer transformation:
oChange in pH oLoss of ligands due to dilution, dissociation of allosteric ligands oEndogenous chelator removes the His B10 Zn2+ ions

2 E subunits linked by disulfide bonds to 2 Fsubunits Insulin binds to Esubunits Causes autophosphorylation of F subunits within plasma Activates catalytic activity of receptor Phosphorylates a number of intracellular proteins

Insulin

Insulin has 4 basic formulations:

1. Ultra short-acting (eg, lispro, aspart, glulisine) 2. Traditional short-acting (eg, regular, soluble), 3. Medium-acting or intermediate-acting (eg, isophane, lente, detemir), and 4. Long-acting (eg, ultralente, glargine).

Lispro (Humalog): B28 and B29 amino acids reversed Aspart (Novolog): B28 replaced with Asp Glulisine (Apidra): B3 replaced with Lys, B29 replaced by Glu Inhibiting the molecule's natural tendency to form hexamers by selfassociation, means better, faster absorption, more rapid onset and peak, and shorter duration

No alteration in structure of human insulin Insulin present in hexameric and monomeric form Fast absorption of the insulin is due to the monomeric form already present Does not peak until 1 to 2 hours later because hexameric form must be converted to monomeric form Lasts about 4 to 6 hours in body

MediumMedium-acting or intermediate-acting intermediate-

Neutral Protamine Hagedorn Protamine and Zinc added to the insulin structure These additions resulted in more of the hexameric form present in the mixture than the monomeric form Thus, more hexamers had to be transformed to monomers for insulin absorption The duration, onset, and peak of the insulin prolonged

Additi f sitiv ly c arg d a i acids Is l ctric i t f a i s li is at H . Is l ctric i t f i s li glargi is at H . Sol l i acidic vironment, formulated to a H of Forms microprecipitate after injection ecause of neutral pH environment  rystals slowly dissolve slow release of insulin dimers and monomer to tissue and lood stream Very little peak

 4 t y p e s o f p o s s i b l e i n j e c t i o n re g i m e n s ex i st , a s fo l l o w s : 1. Twice-daily combinations of short-acting & Twiceshortintermediateintermediate-acting insulin. 2. Multiple injection regimens using once-daily or twiceregimens, daily injections of long-acting or intermediate-acting insulin and short-acting insulins given at each meal 3. A combination of the above 2 regimens, with a morning regimens, injection of mixed insulin, an afternoon premeal injection of short-acting insulin and an evening injection shortof intermediate-acting or long-acting insulin intermediatelong4. Continuous subcutaneous insulin infusion (CSII) using an insulin pump

 Daily Injections
Bolus insulin Basal insulin Two to five shots a day

Insulin Pump Therapy

Constant insulin delivery One insulin type become the bolus insulin and the basal insulin Catheter changed every three days

 Conduct a structured examination and review at least once annually to examine the patient for possible complications. Examination and review should include the following: 1. Growth assessment 2. Injection site examination 3. Examination of hands, feet, and peripheral pulses for signs of limited joint mobility, peripheral neuropathy, and vascular disease 4. Evaluation for signs of associated autoimmune disease 5. Blood pressure

Education is a continuing process involving the child, family, and all members of the diabetes team. The following strategies may be used:
1. Formal education sessions in a clinic setting 2. Opportunistic teaching at clinics or at home in response

to crises or difficulties such as acute illness

3. Therapeutic camping or other organized events 4. Patient-organized meetings

Diabetic Ketoacidosis Fat break down accelerates and increase the production of fatty acids Fatty acids converted into ketone bodies Ketones are toxic at high levels Symptoms - rapid, deep breathing, polyuria, nausea, vomiting, abdominal pain, altered states of mind such as hostility, mania, confusion, lethargy, and hypotension, coma, death Hypoglycemia Low blood sugar, too much insulin or not enough glucose to cover insulin treatment Symptoms - sympathetic activation of the autonomic nervous system: immobilized panic, dread, agitated, sweaty, seizures Amputations Heal slowly Fail to heal Infection Vascular diseases Damage to blood vessels
Diabetic retinopathy growth of poor quality new blood vessels in retina, retinal damage, blindness Diabetic nephropathy damage to kidney, chronic renal failure dialysis Coronary artery disease, stroke, peripheral vascular, diabetic myonecrosis ( muscle wasting )

Damage to arteries

Diabetic foot neuropathy and arterial disease

Type 1 DM is associated with a high morbidity & premature mortality. More than 60% of patients with type 1 DM fare reasonably well over the long term. Many of the rest develop

Blindness, End-stage renal disease, and, In some cases, early death.

The morbidity and mortality associated with diabetes are related to the short- and longterm complications Factors affecting long-term outcomes are  the patient s education, awareness, motivation, and intelligence level.

Some Complications include Hypoglycemia and hyperglycemia, Increased risk of infections, Microvascular complications (eg, retinopathy, nephropathy), Neuropathic complications, and Macrovascular disease

As a result of these complications, people with diabetes have an increased risk of developing

Ischemic heart disease, Cerebral vascular disease, Peripheral vascular disease with gangrene of lower limbs, Chronic renal disease, Reduced visual acuity and blindness, and Autonomic and peripheral neuropathy.

Conclusions
Diabetes is a rapidly increasing disease Controlling diabetes is extremely important for good health Control for type 1 diabetes must be obtained by insulin administration The hexamer form of the insulin molecule is a very important aspect in designing insulin analogues Several insulin analogues can be used in conjuction for treatment Recent developments offer better control but much research is still needed to help control diabetes and possibly find a cure for it

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