D.M

Introduction to Diabetes mellitus TUCOM Internal Medicine 3rd year Dr. Hasan.I.Sultan

Diabetes mellitus
Is a heterogeneous group of metabolic diseases that are characterized by chronic hyperglycemia and disturbances in carbohydrate, lipid, and protein metabolism resulting from defects in insulin secretion and/or insulin action, which can leads to serious complications.Insulin is an anabolic hormone with profound effects on the metabolism of carbohydrate, fat and protein. Insulin is secreted from pancreatic β cells into the portal circulation, with a brisk increase in response to a rise in blood glucose.

Endocrine function of pancreas

A(α) cells produce glucagon; Glucagon is a catabolic hormone. It mobilizes glucose, fatty acids and amino acids from stores into the blood. B(β) cells produce insulin; Insulin is an anabolic hormone, that increases the storage of glucose, fatty acids and amino acids in cells and tissues. Composed of 2 polypeptide chains linked by disulphide bridges. Secreted as proinsulin and transformed to active form, insulin, by cleaveage of C peptide by protease enzymes. D(δ) cells produce somatostatin; Somatostatin may regulate, locally, the secretion of the other pancreatic hormones.

Some characteristics of normal insulin secretion are shown in the table. Insulin lowers blood glucose by suppressing hepatic glucose production and stimulating glucose uptake in skeletal muscle and fat, mediated by the glucose transporter, GLUT 4. Insulin stimulates lipogenesis and inhibits lipolysis, so preventing fat catabolism. Partial oxidation of FFAs in the liver provides energy to drive gluconeogenesis and also produces ketone bodies (acetoacetate, which can be reduced to 3-hydroxybutyrate or decarboxylated to acetone) which are generated in hepatocyte mitochondria.

Insulin deficiency can lead to hyperglycemia and many metabolic derangements which occur mainly in type 1 DM that can leads to death if not treated correctly.

Major metabolic pathways of fuel metabolism and the actions of insulin

A- The normal adult pancreas contains about 1 million islets which are scattered throughout the exocrine parenchyma. Histology is shown in B- The core of each islet consists of β cells that produce insulin, and is surrounded by a cortex of endocrine cells that produce other hormones including glucagon (α cells), somatostatin (δ cells).

C- Pro-insulin in the pancreatic β cell is cleaved to release insulin and equimolar amounts of inert C-peptide (connecting peptide). Measurement of C-peptide can be used to assess endogenous insulin secretory capacity. D- An acute first phase of insulin secretion occurs in response to an elevated blood glucose, followed by a sustained second phase.


AETIOLOGICAL CLASSIFICATION OF DIABETES MELLITUS
Type 1 diabetes Immune-mediated , Idiopathic
Other specific types Genetic defects of β-cell function(MODY) Pancreatic disease (e.g. pancreatitis, pancreatectomy, neoplastic disease, cystic fibrosis, haemochromatosis) Excess endogenous production of hormonal antagonists to insulin (e.g. growth hormone-acromegaly; glucocorticoids-Cushing's syndrome; glucagon-glucagonoma; catecholamines- phaeochromocytoma; thyroid hormones-thyrotoxicosis) Drug-induced (e.g. corticosteroids, thiazide diuretics, phenytoin) Viral infections (e.g. congenital rubella, mumps, Coxsackie virus B) Uncommon forms of immune-mediated diabetes(LADA) Associated with genetic syndromes (e.g. Down's syndrome; Klinefelter's syndrome; Turner's syndrome; DIDMOAD (Wolfram's syndrome)-diabetes insipidus, diabetes mellitus, optic atrophy, nerve deafness; Friedreich's ataxia; myotonic dystrophy) Gestational diabetes
Type 2 diabetes

AETIOLOGY AND PATHOGENESIS OF DIABETES

In both of the common types of diabetes, environmental factors interact with genetic susceptibility. TYPE 1 DIABETES: Is a slowly progressive T cell-mediated autoimmune disease, destruction of the insulin-secreting cells in the pancreatic islets takes place over many years. Hyperglycaemia accompanied by the classical symptoms of diabetes occurs only when 70-90% of β cells have been destroyed.

'insulitis' , infiltration of the islets with mononuclear cells containing activated macrophages. the initial patchiness of this lesion. the striking β-cell specificity of the destructive process, with the glucagon and other hormone-secreting cells in the islet invariably remaining intact.

Type 1 diabetes is associated with other autoimmune disorders, including thyroid disease, coeliac disease, Addison's disease, pernicious anaemia and vitiligo.Environmental factors; Viral infection cause autoimmune damage to β-cells, including mumps, Coxsackie B4, retroviruses, rubella (in utero), cytomegalovirus and Epstein-Barr virus. Bovine serum albumin (BSA), a major constituent of cow's milk. Various nitrosamines Stress

TYPE 2 DIABETES: More complex; is a combination of resistance to the actions of insulin in liver and muscle together with impaired pancreatic β-cell function leading to 'relative' insulin deficiency. Coexisted with 'metabolic syndrome‘.Pathological changes; is deposition of amyloid. LADA: Latent autoimmune diabetes of adult, is form of type 1 DM occur in middle aged patients.MODY: Maturity onset diabetes of young, is a rare autosomal form of type 2 DM (less than 5% of cases of DM) affecting young people with positive family history.

In the early stage of the disorder the response to progressive insulin resistance is an increase in insulin secretion by the pancreatic cells, causing hyperinsulinaemia. Eventually the β cells are unable to compensate adequately and blood glucose rises, producing hyperglycaemia. With further β-cell failure (type 2 diabetes) glycaemic control deteriorates and treatment requirements escalate.

Comparison of the Two Types of Diabetes Mellitus

SYMPTOMS OF HYPERGLYCAEMIA Thirst, dry mouth Polyuria Nocturia Tiredness, fatigue Recent change in weight Blurring of vision Pruritus vulvae, balanitis (genital candidiasis) Nausea; headache Hyperphagia; predilection for sweet foods Mood change, irritability, difficulty in concentrating, apathy


Investigations
1- URINE TESTING: Glucose; By using sensitive glucose-specific dipsticks 1-2 hours after a meal since this will detect more cases of diabetes than a fasting specimen. Ketones; By using dipsticks for ketones. Ketonuria is not pathognomonic of diabetes but, if associated with glycosuria, the diagnosis of diabetes is highly likely.

Protein; Dipstick testing for albumin. This will detect urinary albumin greater than 300 mg/l. Smaller amounts of urinary albumin from 30 to 300 mg/24 hours (microalbuminuria) can be measured by special kit and these provide indicators of the risk of developing diabetic nephropathy.

2- Blood testing

Glucose; In general, venous plasma values are the most reliable for diagnostic purposes. Glycated haemoglobin(HbA1c); provides an accurate and objective measure of glycaemic control over a period of weeks to months but is not sufficiently sensitive to make a diagnosis HbA1c estimates may be erroneously diminished in anaemia or during pregnancy, and may be difficult to interpret in uraemia or a haemoglobinopathy. Glycated serum proteins ('fructosamine') can be measured used in diabetic pregnancy.

Blood lipids; Serum lipids-total cholesterol, low-density and high-density lipoprotein (LDL and HDL) cholesterol and triglyceride-is another important index of overall metabolic control. Oral glucose tolerance test (OGTT) Done when there is doubt about diagnosis of DM Plasma glucose measured before, and 2 hrs after, 75 g glucose load taken orally.

With normoglycemia, a relatively small amount of serum protein is glycated.

With persistent hyperglycemia, increased protein glycation occurs.

Management

1-Educating patients; Understand their condition. Those requiring insulin need to learn how to measure their dose of insulin accurately with an insulin syringe or pen device, to give their own injections and to adjust the dose themselves on the basis of blood glucose values and other factors such as exercise, illness and episodic hypoglycaemia. Familiar with the symptoms of hypoglycaemia . Self-assessment of glycaemic control. Diet= decrease saturated fat , decrease sugar intake, increase starch , moderate protein intake. Smoking cessation. Foot care. Preconception advice. Regular exercise .


A 'plate model' for meal planning. The plate is divided into three sections. The smallest section (one-fifth of total area) is for the meat, fish, eggs or cheese, and the remainder divided in roughly equal proportions between the staple food (rice, pasta, potatoes, bread etc.) and vegetables or fruit.



ORAL ANTI-DIABETIC DRUGS
1- SULPHONYLUREAS; Mechanism of action; The principal effect of sulphonylureas is to stimulate the release of insulin from the pancreatic β cell. Indications for use Sulphonylureas are valuable in the treatment of non-obese patients with type 2 diabetes who fail to respond to dietary measures alone.The first-generation; Tolbutamide, Chlorpropamide.The second-generation; gliclazide and glipizide cause few side-effects, but glibenclamide is prone to induce severe hypoglycaemia and should be avoided in the elderly.

Newer long-acting preparations such as glimepiride and a modified-release form of gliclazide can be administered once daily with no apparent increased risk of hypoglycaemia. Primary treatment failures; People with type 2 diabetes who fail to respond to initial treatment with sulphonylureas. Secondary failure; (i.e. after a period of satisfactory glycaemic control)

2- BIGUANIDES; Metformin is the only biguanide available. Mechanism of action; It has no hypoglycaemic effect in non-diabetic individuals, but in diabetes, insulin sensitivity and peripheral glucose uptake are increased. Indications for use; metformin is not associated with a rise in body weight and it is therefore preferred for the obese patient. In addition, It has a synergistic with sulphonylurea drugs, the two can be combined when either alone has proved inadequate.


3- ALPHA-GLUCOSIDASE INHIBITORS; which delay carbohydrate absorption in the gut by selectively inhibiting disaccharidases. Acarbose or miglitol is available and is taken with each meal. Both lower post-prandial blood glucose and modestly improve overall glycaemic control. They can be combined with a sulphonylurea. The main side-effects are flatulence, abdominal bloating and diarrhoea.


4- THIAZOLIDINEDIONES; (glitazones) work by enhancing the actions of endogenous insulin. For use Rosiglitazone or pioglitazone are usually prescribed as second-line therapy with sulphonylureas in patients intolerant of metformin, or as third-line therapy in combination with sulphonylurea and metformin. However, their use as monotherapy and in combination with insulin is likely to increase. side-effects; liver dysfunction, sodium and fluid retention, must be avoided in patients with cardiac failure.


5- MEGLITINIDES AND AMINO ACID DERIVATIVES; These drugs are called prandial glucose regulators. Repaglinide directly stimulates endogenous insulin secretion and is taken immediately before food. It is less likely to cause hypoglycaemia than sulphonylureas. Nateglinide has a similar mode of action, restores first-phase insulin secretion, and is prescribed with metformin.

COMBINED ORAL ANTI-DIABETIC THERAPY AND INSULIN In diabetic patients who are requiring increasing doses of a sulphonylurea or biguanide, either alone or in combination with each other or with a thiazolidinedione, the introduction of a single dose of an intermediate- or long-acting insulin (usually isophane), administered at bedtime, may improve glycaemic control and delay the development of overt pancreatic β-cell failure.

INCRETIN MIMETICS Is an incretin hormone which stimulates insulin secretion in a glucose-dependent manner that present in the gut, thus hypoglycaemia is unlikely. A new class of therapeutic agents is being developed for treatment of type 2 diabetes.

INSULIN

Manufacture and formulation; Insulin was discovered in 1921, and obtained from animal sources (bovine and porcine insulin). After 1980, the use of recombinant DNA technology has enabled large-scale production of human insulin. Recently, rDNA and protein engineering techniques that alter the amino acid sequence of insulin have been used to produce 'monomeric' analogues of insulin, which are more rapidly absorbed from the site of injection (e.g. insulin lispro or aspart).

Duration of action (in hours) of insulin preparations

Insulin
Onset
Peak
Duration
Rapid-acting (insulin analogues-lispro, aspart, glulisine)
< 0.5
0.5-2.5
3-4.5
Short-acting (soluble (regular))
0.5-1
1-4
4-8
Intermediate-acting (isophane (NPH), lente)
1-3
3-8
7-14
Long-acting (bovine ultralente)
2-4
6-12
12-30
Long-acting (insulin analogues- glargine, detemir)
1-2
None
18-24

Duration of action (in hours) and types of insulin

Rapid-acting
Short-acting
Intermediate-acting
Long-acting insulin analogues
Mixed insulin

Insulin delivery

The strength of insulin is 100 u/ml. 1-Subcutaneous injection; the most common rout, into the anterior abdominal wall, upper arms, outer thighs and buttocks. Used in: Type 1 DM Type 2 DM; in combination with OHA, pregnant woman, or sever illness or major surgery require hospital admission. Gestational DM. By using a battery-powered portable insulin pump or a disposable plastic syringe with a fine needle (which can be reused several times), or pen device.

2-Intramuscular injection or I.V. infusion: use just soluble insulin or rapidly acting insulin analogue, by using infusion pump providing continuous intravenous infusion of insulin. Use in treatment of DKA or NKHDC. 3-Other rout; intraperitoneal inj. in patient on peritoneal dialysis.

SIDE-EFFECTS OF INSULIN THERAPY Hypoglycaemia Weight gain Peripheral oedema (insulin treatment causes salt and water retention in the short term) Insulin antibodies (animal insulins) Local allergy (rare) Lipodystrophy at injection sites

Local allergy

Insulin regimens
Twice-daily administration of a short-acting and intermediate-acting insulin (usually soluble and isophane insulins), given in combination before breakfast and the evening meal, is the simplest regimen and is still commonly used. Individual requirements vary considerably but usually two-thirds of the total daily requirement of insulin is given in the morning in a ratio of 1:2, short:intermediate-acting insulins. The remaining third is given in the evening, and doses are adjusted according to blood glucose monitoring.


Multiple injection regimens are popular, with short-acting insulin being taken before each meal, and intermediate-acting insulin being injected at bedtime (basal-bolus regimen). This type of regimen allows greater freedom of timing of meals and is of value to individuals with variable day-to-day activities, but snacks may have to be taken between meals to prevent hypoglycaemia.


Once-daily injections rarely achieve satisfactory glycaemic control and are reserved either for some elderly patients or for those who retain substantial endogenous insulin secretion and have a low insulin requirement. Honey moon period; The pancreas of patient with type 1 DM may partially recover after the initial diagnosis resulting in decrease insulin requirement.

Complications of diabetes mellitus