diabetes milletus
DESCRIPTION
group 4 report on Medical biochemistryTRANSCRIPT
Diabetes MEllItus
Group IVBustos Precious Rose
Cabantac, Rhea KatherineCabungcal, Kristine
Cada, Kristel JoyCada, Kristian
Caeg, Anne ClarisseCalupig, Tiffany
At the end of this report, the class will be able to:
1. Know the biosynthesis of InsulinSpecifically: Its release from Beta cells; Its role in Carbohydrates, Protein, and Fat
Metabolism; Its relationship with glucagon, epinephrine,
and cortisol;
2. What Diabetes Milletus is and its causes;3. The clinical types of Diabetes Milletus;4. The mechanism behind the development of
Polyuria, Polydipsia and Polyphagia in DM;5. The biochemical events that lead to the
formation of HbA1c;6. The complications in DM and the end- organ
damage, and;7. The treatment in DM.
BIOSYNTHESIS OF INSULIN AND ITS
RELEASE FROM BETA CELLS
Cada, Kristian C.
BIOSYNTHESIS OF INSULIN
RELEASE FROM BETA CELLS
HOW INSULIN WORKS
Insulin’s role in carbohydrates, fats
and protein metabolism
CAEG, ANNE CLARISSE A.
Insulin and Carbohydrate Metabolism
• Glucose is liberated from dietary carbohydrate such as starch or sucrose by hydrolysis within the small intestine, and is then absorbed into the blood.
• Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells throughout the body to stimulate uptake, utilization and storage of glucose.
• The effects of insulin on glucose metabolism vary depending on the target tissue.
Insulin and Carbohydrate Metabolism
• Two important effects are:1. Insulin facilitates entry of glucose
into muscle, adipose and several other tissues. the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin.
Insulin and Carbohydrate Metabolism
2. Insulin stimulates the liver to store glucose in the form of glycogen.
large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen.
(+) hexokinase, phosphofructokinase and glycogen synthase glycogen synthesis
(-) glucose-6-phosphatase
Physiologic Action of Insulin on CHO Metabolism
ACTION TISSUE
Glucose transport Increase Muscle, adipose tissue
Glycolysis Increase Muscle, adipose tissue
Glycogen synthesis Increase Liver muscle, adipose tissue
Glycogen degradation Decrease Liver muscle, adipose tissue
Gluconeogenesis Decrease Liver and kidney
Insulin and Lipid Metabolism
• Insulin promotes synthesis of fatty acids in the liver
• Insulin inhibits breakdown of fat in adipose tissue
• From a whole body perspective, insulin has a fat-sparing effect.
Physiologic Action of Insulin on Lipid Metabolism
ACTION TISSUE
Lipolysis Decrease Adipose tissue
Synthesis of FA and TAG Increase Liver, adipose tissue
Synthesis of VLDL Increase Liver
Lipoprotein lipase activity Increase Adipose tissue
Fatty acid oxidation Decrease Muscle, liver
Cholesterol formation Increase Liver
Physiologic Action of Insulin on CHON Metabolism
ACTION TISSUE
Amino acid transport Increase Muscle, liver, adipose tissue
Protein synthesis Increase Muscle, liver, adipose tissue
Protein degradation Decrease Muscle
Urea synthesis Decrease Liver
Insulin’s relationship with glucagon
Glucagon • is a hormone, secreted by the pancreas, that
raises blood glucose levels. • The pancreas releases glucagon when blood
glucose levels fall too low. • Glucagon causes the liver to convert stored
glycogen into glucose, which is released into the bloodsteam.
Insulin’s relationship with glucagon
• Glucagon also stimulates the release of insulin, so that glucose can be taken up and used by insulin-dependent tissues.
• Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels at the right level.
Insulin’s relationship with epinephrine
• Epinephrine acts by binding to a variety of adrenergic receptors. Binding to α-adrenergic receptors inhibits insulin secretion by the pancreas,
• (+) glycogenolysis in the liver and muscle, and glycolysis in muscle.
Insulin’s relationship with epinephrine
• β-Adrenergic receptor binding triggers glucagon secretion in the pancreas, increased adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and increased lipolysis by adipose tissue.
• Results to an increase blood glucose and fatty acids
Insulin’s relationship with cortisol
• Cortisol counteracts insulin, contributes to hyperglycemia-causing hepatic gluconeogenesis and inhibits the peripheral utilization of glucose (insulin resistance) by decreasing the translocation of glucose trasporters (especially GLUT4) to the cell membrane.
• (+)glycogen synthesis (glycogenesis) in the liver.
DIABETES MILLETUS
Calupig, Tiffany Grace
Diabetes mellitus
• is a group of metabolic diseases characterized by hyperglycemia. This can result from defects in insulin secretion, defects in insulin receptor and action, or both.
• Because glucose is a chemically reactive molecule, the chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and, ultimately, failure of various organs.
• The most pronounced symptoms are those of the syndrome known as the “3Ps”.
• classic symptoms: including polyuria (frequent urination), polydipsia (frequent water drinking) and polyphagia (an insatiable hunger).
CLINICAL TYPES OS DIABETES MELLITUS
• Type 1 Diabetes Mellitus• Type 2 Diabetes Mellitus• Type (3) Diabetes Mellitus
• Type 1 diabetes (formerly referred to as juvenile onset diabetes mellitus and insulin-dependent diabetes mellitus) results from destruction of beta cells and a complete or near total absence of insulin synthesis.
• Insulin is the primary hormone responsible for regulating glucose metabolism and in signalling for the utilization and storage of basic nutrients
• insulin acts as a powerful anabolic hormone, and it is also a potent inhibitor of the catabolic processes evoked by the counter regulatory hormones (i.e., glucagon, epinephrine, cortisol, and growth hormone).
• Although the important target tissues for insulin are liver, muscle, and fat, insulin has pleiotropic effects on cell growth and metabolism in many tissues (Kahn, 2001).
• The development of type 1 diabetes is the culmination of a chronic autoimmune destruction of the pancreatic β-cells that occurs over many years.
• This process results in severe, and ultimately complete, insulin deficiency.
• In addition, insulin deficiency results in the unrestrained lipolysis and increased ketogenesis that leads to diabetic ketoacidosis.
• Type 1 diabetes accounts for approximately 10% of all patients diagnosed with diabetes mellitus. It is a major chronic disease of children and is now being recognized with increasing frequency in adults.
• In the absence of insulin, the resulting metabolic derangements in acute diabetic ketoacidosis eventually lead to coma and death.
• Approximately 90% of diabetics have type 2 diabetes mellitus rather than type 1.
• Type 2 diabetes (previously called maturity-onset diabetes), is characterized by insulin resistance.
• These patients initially exhibit impaired glucose uptake into tissues and a compensatory increase in insulin secretion.
• Although type 2 diabetes usually occurs in people over 40 years of age, its incidence has been increasing markedly in younger individuals over the past decade.
• Type 2 diabetes is often accompanied by hypertension and dyslipidemia (abnormalities in blood lipoproteins) and most of these patients are obese. Long term compensatory increase in insulin secretion frequently leads to pancreatic failure and most patients with type 2 diabetes eventually require insulin.
Type 3 Diabetes Mellitus Gestational diabetes
• Gestational diabetes mellitus (GDM) resembles type 2 diabetes in several respects, involving a combination of relatively inadequate insulin secretion and responsiveness.
• It occurs in about 2%–5% of all pregnancies and may improve or disappear after delivery. Gestational diabetes is fully treatable but requires careful medical supervision throughout the pregnancy. About 20%–50% of affected women develop type 2 diabetes later in life.
• Even though it may be transient, untreated gestational diabetes can damage the health of the fetus or mother.
• Risks to the baby include macrosomia (high birth weight), congenital cardiac and central nervous system anomalies, and skeletal muscle malformations. Increased fetal insulin may inhibit fetal surfactant production and causes respiratory distress syndrome.
FACTORS CAUSING DIABETES MELLITUS
• The typical pancreatic lesion of type 1 diabetes is the selective loss of almost all β-cells, whereas other islet cell types (α, δ, and pancreatic polypeptide cells) remain intact.
• The most common mechanism for β-cell destruction is thought to be autoimmune-mediated inflammatory damage.
• It has been long-recognized that heredity is a major factor in diabetes.
• Environmental factors and lifestyle also play a role in the development of clinical diabetes.
• Environmental factors that have been implicated include certain foods (including cow’s milk), and common viruses.
• The exception is exposure to wild-type rubella virus during the first trimester of pregnancy. As many as 20% of the children born after prenatal exposure to rubella later develop type 1 diabetes.
Following is a comprehensive list of other causes of diabetes:
• Genetic defects of β-cell Function – Maturity onset diabetes of the young (MODY)– Mitochondrial DNA mutations
• Genetic defects in insulin processing or insulin action
– Defects in proinsulin conversion– Insulin gene mutations– Insulin receptor mutations
• Exocrine Pancreatic Defects – Chronic pancreatitis– Pancreatectomy– Pancreatic neoplasia– Cystic fibrosis– Hemochromatosis– Fibrocalculous pancreatopathy
• Endocrinopathies – Growth hormone excess (acromegaly)– Cushing syndrome– Hyperthyroidism– Pheochromocytoma– Glucagonoma
• Infections – Cytomegalovirus infection– Coxsackievirus B
• Drugs – Glucocorticoids– Thyroid hormone– β-adrenergic agonists
POLYURIA,POLYDIPSIA and POLYPHAGIA
CADA, Kristel Joy S.
POLYURIA
• condition usually defined as excessive or abnormally large production and/or passage of urine
• Frequent urination• may also be termed diuresis. • appears in conjunction with polydipsia
(increased thirst)
POLYURIA in Diabetes Mellitus
• Diabetes mellitus – disorder of blood glucose regulation, which results
from a deficiency in the action of the hormone insulin– autoimmune destruction of the insulin-secreting cells
of the pancreas (type 1 diabetes mellitus) – problem in the responsiveness of tissues to insulin,
known as insulin resitance (type 2 diabetes mellitus– hyperglycemia, or high levels of glucose in the
plasma
HYPERGLYCEMIA
• Hyperglycemia–causes excessive urine production
• URINE PRODUCTION involves filtration and reabsortion.
Urine Production
• first step in the production of urine is a process called filtration
• there is bulk flow of water and small molecules from the plasma into Bowman’s capsule (the first part of the nephron).
• nonspecific nature of filtration, useful small molecules such as glucose, amino acids, and certain ions end up in the forming urine, which flows into the kidney tubules
• To prevent the loss of these useful substances from the body, the cells lining the kidney tubules transfer these substances out of the forming urine and back into the extracellular fluid. This process is known as reabsorption
Filtration and Reabsorption.
• Under normal circumstances, 100% of the glucose that is filtered is reabsorbed
• Glucose reabsorption involves transport proteins that require specific binding
• diabetic that has hyperglycemia– filtered load of glucose (amount of glucose filtered)
can exceed the capacity of the kidney tubules to reabsorb glucose, because the transport proteins become saturated
– result is glucose in the urine
Glucose is a solute that draws water into the urine by osmosis. Thus,
hyperglycemia causes a diabetic to produce a high volume of glucose-
containing urine.
Normal Glucose Handling and Polyuria
POLYDIPSIA
• medical symptom in which the patient displays excessive thirst
• symptom is characteristically found in diabetics
• appears in conjunction with POLYURIA
• caused by a change in the osmolality of the extracellular fluids of the body, hypokalemia, decreased blood volume (as occurs during major hemorrhage), and other conditions that create a water deficit
• usually a result of OSMOTIC DIURESIS
POLYPHAGIA
• Excessive hunger or increase in appetite • abnormal behavior of eating or the need to
eat• a common symptom of diabetes• referred to as disorder of hyperalimentation
commonly associated with diabetes
• causative factors of polyphagia or hyperphagia are depression, uncontrolled diabetes, increased exercise, growth spurt, injury to the hypothalamus, medication and drugs and bulimia nervosa.
• Insulin is the hormone that regulates the blood glucose levels– produced by the islets of Langerhans in the
pancreas– Patients with diabetes mellitus also experience
excessive thirst (polydipsia) and increase in urine output (polyuria)
– hyperglycemia
• Hyperglycemia– Lack of insulin results in increased blood glucose
levels– This is not used for energy and causes starvation
of the cells– sugar build up is passed out in the urine– results in loss of energy and the person is again
hungry
Build up of glucose in the bloodstreaqm
• Cabungcal, Kristine Mae
Diagnostic Procedures
Diagnostic Procedures:
• Fasting Plasma Glucose (FPG)• Oral Glucose Tolerance Test (OGTT)• Random Plasma Glucose Test
Table 1. 2006 WHO Diabetes criteriaCondition
2 hour glucose
Fasting glucose
mmol/l(mg/dl)
mmol/l(mg/dl)
Normal <7.8 (<140)
<6.1 (<110)
Impaired fasting glycaemia <7.8 (<140)
≥ 6.1(≥110) & <7.0(<126)
Impaired glucose tolerance ≥7.8 (≥140) <7.0 (<126)
Diabetes mellitus ≥11.1 (≥200) ≥7.0 (≥126)
Fasting Plasma Glucose done to measure the blood glucose in a person who has not eaten anything for at least 8
hours. This test is used to detect diabetes and pre-diabetes The FPG test is said to be most reliable when done in the morning.
Table 2. FPG test Plasma Glucose Result (mg/dL)
Diagnosis
99 or below Normal
100 to 125 Pre-diabetes(impaired fasting glucose)
126 or above Diabetes
Source: NDIC, 2008
Oral Glucose Tolerance Test (OGTT)
OGTT is more sensitive than the FPG test for diagnosing pre-diabetes requires fasting for at least 8 hours before the test and 2 hours after the person is made to drink a glucose-containing
beverage. The plasma glucose level is measured immediately before and 2 hours after a person drinks a liquid containing 75 grams of
glucose dissolved in water.
Table 3. OGTT 2-Hour Plasma Glucose Result (mg/dL)
Diagnosis
139 and below Normal
140 to 199 Pre-diabetes(impaired glucose tolerance)
200 and above Diabetes
Source: NDIC, 2008
Random Plasma Glucose Test
casual plasma glucose test which measures blood glucose without regard to when the person being tested last ate.
This test, along with an assessment of symptoms, is used to diagnose diabetes but not pre-diabetes.
blood glucose level of 200 mg/dL increased urination increased thirst unexplained weight loss
Summary of Diagnostic Procedures that confirms positive for diabetes mellitus
Test Level
Fasting plasma glucose level ≥7.0mmol/L (126mg/dL)
Plasma glucose ≥11.1mmol/L (200mg/dL) two hours after a 75g oral glucose load as in a glucose tolerance test
Symptoms of hyperglycemia and casual plasma glucose
≥11.1mmol/L (200mg/dL)
Glycated hemoglobin HbA1C ≥6.5%
Formation of HbA1c
HbA1c Hemoglobin A1c is a minor component of hemoglobin to
which glucose is bound. HbA1c is also sometimes referred to as glycosylated or glycosylated hemoglobin or glycohemoglobin.
HbA1c is a form of hemoglobin used primarily to identify the average plasma glucose concentration over prolonged periods of time. It is formed in a non-enzymatic glycation pathway by hemoglobin's exposure to plasma glucose. Normal levels of glucose produce a normal amount of glycated hemoglobin. As the average amount of plasma glucose increases, the fraction of glycated hemoglobin increases in a predictable way.
• Higher amounts of glycated hemoglobin, indicating poorer control of blood glucose levels, have been associated with cardiovascular disease, neuropathy and retinopathy. Monitoring the HbA1c in Type-I diabetic patients may improve treatment (Larsen et al., 1990).
Controlled diabetes:not much glucose, not much glycosylated haemoglobin
Uncontrolled diabetes: more glucose, much more glycosylated haemoglobin
HbA1c HbA1c levels depend on the blood glucose concentration in which the
higher the glucose concentration in blood, the higher the level of HbA1c. Not influenced by daily fluctuations in the blood glucose concentration
but reflect the average glucose levels over the prior six to eight weeks. Thus, HbA1c is a useful indicator of how well the blood glucose level has been controlled over the duration of 2-3 months.
Table for HbA1c Level
HbA1c level Diagnosis
>6.5% diabetes
<6.0% not diabetic
in between....6.0-6.5 pre-diabetes or at risk of diabetes
Limitations to HbA1c Cannot be used to monitor day-to-day blood
glucose concentrations to adjust insulin doses Cannot detect the day-to-day presence or absence
of hyperglycemia or hypoglycemia May increase falsely in: uremia (kidney failure),
chronic excessive alcohol intake, and hypertriglyceridemia.
May falsely decrease in: acute or chronic blood loss, sickle cell disease or thalassemia.
What are the complications of DM(end organ damage)?
Bustos, Precious Nikki
group of cells that need insulin:• those in muscle, liver, and fat• do not become exposed to high internal
glucose levels when the blood sugars are high and insulin levels are low. The lack of insulin slows the movement of glucose into these cells
• cells such as those in the brain, nervous system, heart, blood vessels and kidneys pick up glucose directly from the blood without using insulin.
• reason why damage tends to occur in these areas of the body (nerve and kidney cells, and in small blood vessels like those in the eyes.)
Complications of Diabetes Mellitus:
1.Cardiovascular Disease– 20% of patients with CVD are Diabetics.– 75% of these patients died due to CVD– magnified by high blood sugars
Complications of Diabetes Mellitus:
2.Nephropathy– Usually begins as recurrent UTI– Urinalysis: presence of rbc, protein, sugar. – when people have had diabetes > 10 years– Diabetes is the most common cause of kidney
failure in some parts of the world, where it may affect as many as 40% of dialysis patients.
Complications of Diabetes Mellitus:
3.Retinopathy– Usually there is blurry vision– Retinopathy may lead to permanent blindness.
Complications of Diabetes Mellitus:
4.Neuropathy– Usually there is numbness on extremities– longest nerves going to the feet are the first to be
damaged – Occasionally there is “tingling sensation”– Worse is loss of sensation
Complications of Diabetes Mellitus:
5. Skin Infections– There is itchiness– There is drying of skin– Recurrent wounds/ non healing wounds
Non healing wound/diabetic ulcer
Non healing wound/diabetic ulcer
Non healing wound/diabetic ulcer
Ulcers with gangrene
Tissue or Organ Affected
What Happens Complications
Blood vessels Fatty material (atherosclerotic plaque) builds up and blocks large or medium-sized arteries in the heart, brain, legs, and penis.The walls of small blood vessels are damaged so that the vessels do not transfer oxygen to tissues normally, and the vessels may leak.
Poor circulation causes wounds to heal poorly and can lead to heart disorders, strokes, gangrene of the feet and hands, erectile dysfunction (impotence), and infections.
Eyes The small blood vessels of the retina are damaged.
Decreased vision and, ultimately, blindness occur.
Kidney Blood vessels in the kidney thicken.Protein leaks into urine.Blood is not filtered normally.
The kidneys malfunction, and ultimately, kidney failure occurs.
Long Term Complications of DM
Nerves Nerves are damaged because glucose is not metabolized normally and because the blood supply is inadequate.
Legs suddenly or gradually weaken.
People have reduced sensation, tingling, and pain in their hands and feet.
Autonomic nervous system
The nerves that control blood pressure and digestive processes are damaged.
Swings in blood pressure occur.
Swallowing becomes difficult.
Digestive function is altered, and sometimes bouts of diarrhea occur.
Erectile dysfunction develops.
Skin Blood flow to the skin is reduced, and sensation is decreased, resulting in repeated injury.
Sores and deep infections (diabetic ulcers) develop.
Healing is poor.
Blood White blood cell function is impaired.
People become more susceptible to infections, especially of the urinary tract and skin.
Connective tissue
Glucose is not metabolized normally, causing tissues to thicken or contract.
Carpal tunnel syndrome and Dupuytren's contracture develop.
Treatment of Diabetes Mellitus
Cabantac, Katherine Rhea D.
• Diet Management
• Physical Activity
• Oral Medications
• Insulin injections/pump
Diet Management• Carbohydrates
– Should comprise 60-70% of the calories needed– Fructose should be avoided except those from
fruits• Protein
– Type 2 diabetics has higher than normal protein consumption
• Fat– Saturated fat should be <7% of daily calories– Cholesterol consumption should be <200mg/day
Physical Activity
• Should first undergo cardiovascular disease screening before doing moderate to high intensity exercise
• Type 1 diabetics should monitor their blood glucose level during and after exercise
Oral medications
• Increase insulin production• Sulfonylureas – stimulate the pancreas to secrete insulin• DPP-IV inhibitors – inhibit enzymatic degradation of glucagon like
peptide 1
• Enhance insulin effect• Thiazolidenediones – increases insulin sensitivity
• Reduce blood glucose level• Biguanides – decreases hepatic glucose output
• Interfere with glucose absorption • α glucosidase inhibitor – slows down carbohydrate absorption
Insulin Type (and examples) Onset
(approx.)Peak time(approx.)
Duration(approx.)
Rapid acting•Insulin aspart (NovoLog)•Insulin glulisine (Apidra)•Insulin lispro (Humalog)
5 to 15 minutes
45 to 90 minutes
3 to 4 hours
Short acting•Insulin regular (Humulin R, Novolin R)
30 minutes 2 to 5 hours 5 to 8 hours
Intermediate acting•Insulin NPH (Humulin N, Novolin N)
1 to 3 hours 6 to 12 hours 16 to 24 hours
Long acting•Insulin glargine (Lantus)•Insulin detemir (Levemir)
1 to 4 hours none 20 to 24 hours
FIN