D.M.

Dr.Abdel-Ellah Al-ShudifatMD,MRCP(UK)

Assistant professor,Hashemite UniversityConsultant Internist

28/11/2012

The term diabetes mellitus describes several diseases of abnormal carbohydrate metabolism

that are characterized by hyperglycemia .

It is associated with a relative or absolute impairment in insulin secretion, along with varying degrees of peripheral resistance to the action of insulin.

Type 2 diabetes accounts for over 90 percent of cases of diabetes in the United States, Canada, and Europe; type 1 diabetes accounts for another 5 to 10 percent, with the remainder due to other causes.

• TYPE 1 DIABETES — Type 1 diabetes is characterized by destruction of the pancreatic beta cells, leading to absolute insulin deficiency.

• This is usually due to autoimmune destruction of the beta cells (type 1A). Testing for islet cell antibodies (ICA) or other islet autoantibodies (antibodies to glutamic acid decarboxylase [GAD65], insulin, and to the tyrosine phosphatases, IA-2 and IA-2β, and zinc transporter ZnT8) in serum may be helpful if establishing the diagnosis is important; a positive result is indicative of immune-mediated or type 1A diabetes

• However, some patients with absolute insulin deficiency have no evidence of autoimmunity and have no other known cause for beta-cell destruction.

• They are said to have idiopathic or type 1B diabetes mellitus.

• TYPE 2 DIABETES — Type 2 diabetes is by far the most common type of diabetes in adults and is characterized by hyperglycemia and variable degrees of insulin deficiency and resistance.

• It is a common disorder whose prevalence rises markedly with increasing degrees of obesity.

• Insulin resistance and insulin deficiency can arise through genetic or environmental influences, making it difficult to determine the exact cause in an individual patient.

• In addition, hyperglycemia itself can impair pancreatic beta cell function and exacerbate insulin resistance.

• Maturity onset diabetes of the young — Maturity onset diabetes of the young (MODY) is a clinically heterogeneous disorder characterized by non-insulin dependent diabetes diagnosed at a young age (<25 years) with autosomal dominant transmission and lack of autoantibodies .

• MODY is the most common form of monogenic diabetes, accounting for 2 to 5 percent of diabetes Many patients are misclassified as having either type 1 or 2 diabetes.

• Mutations in hepatocyte nuclear factor-1-alpha (HNF1A) and the glucokinase (GCK) gene are most commonly identified, occurring in 52 to 65 and 15 to 32 percent of MODY cases, respectively . Mutations in HNF4A account for approximately 10 percent of cases.

• The diagnosis of MODY is made by performing diagnostic genetic testing by direct sequencing of the gene.

• DISEASES OF THE EXOCRINE PANCREAS — Any disease that damages the pancreas, or removal of pancreatic tissue, can result in diabetes.

• Cystic fibrosis .• Hereditary hemochromatosis.• ENDOCRINOPATHIES Endocrine abnormalities that can lead to abnormalities in

glucose regulation include:• Cushing's syndrome, due to pituitary or adrenal disease or to exogenous

glucocorticoid administration• Acromegaly• Catecholamine excess in pheochromocytoma• Glucagon-secreting tumors (glucagonomas), associated with an unusual

constellation of other clinical features, including skin rash, weight loss, anemia, and thromboembolic problems

• Somatostatin-secreting tumors (somatostatinomas), typically associated with the triad of diabetes mellitus, cholelithiasis, and diarrhea with steatorrhea

• Hyperthyroidism, which can interfere with glucose metabolism, although overt diabetes is unusual

• DRUG-INDUCED DIABETES — A large number of drugs can impair glucose tolerance;

• they act by decreasing insulin secretion,• increasing hepatic glucose production, • or causing resistance to the action of insulin(Glucocorticoids,Oral

contraceptives,Tacrolimus, sirolimus, and cyclosporine,Nicotinic acid (niacin).HIV protease inhibitors.Thiazide diuretics (primarily at doses above 25 mg/day of hydrochlorothiazide or its equivalent).Atypical antipsychotics (clozapine, and some conventional antipsychotics),Gonadotropin releasing hormone agonists,OtherBeta blockers,Clonidine,Pentamidine,Alcohol

• VIRAL INFECTIONS — Certain viruses can cause diabetes, either through direct beta-cell destruction or, hypothetically, by inducing autoimmune damage.

• Chronic hepatitis C virus infection has been associated with an increased incidence of diabetes, but it is uncertain if there is a cause-and-effect relationship.

• GESTATIONAL DIABETES MELLITUS — Gestational diabetes occurs when a woman's pancreatic function is not sufficient to overcome both the insulin resistance created by the anti-insulin hormones secreted by the placenta during pregnancy (eg, estrogen, prolactin, human chorionic somatomammotropin, cortisol, and progesterone) and the increased fuel consumption necessary to provide for the growing mother and fetus.

• It is estimated to occur in approximately 2.1 percent of pregnant women in the United States, usually developing in the second or third trimester.

• Symptomatic — Symptoms are due to hyperglycemia and commonly include :

• Polyuria.• Polydipsia.• nocturia . • weight loss .• In adolescent girls, vaginal discharge or vulvovaginitis due to

monilial infection can be the initial chief complaint . • Asymptomatic — Many patients with type 2 diabetes are

identified by screening and are asymptomatic at presentation.

• This occurs as a result of screening specifically for type 2 diabetes or because of a positive urinalysis test for glycosuria obtained as part of a routine physical examination.

screening • Indications — • The ADA recommends screening children every three years beginning at 10

years of age or at onset of puberty (whichever comes first) if they are overweight or obese (BMI ≥85th percentile) and have two or more of the following additional risk factors :

• Type 2 DM in a first- or second-degree relative• Member of a high-risk ethnic group: Native American, non-Hispanic black,

Hispanic, Asian American, or Pacific islander• Signs of insulin resistance or conditions associated with insulin resistance

(eg, hypertension, dyslipidemia, acanthosis nigricans, and polycystic ovary syndrome, or small for gestational age birth weight)

• Maternal history of diabetes or gestational diabetes during the child's gestation.

• Test — • Screening for diabetes can be done by measuring

hemoglobin A1C (A1C),• fasting plasma glucose (FPG),• or performing an oral glucose tolerance test (OGTT).• Among candidates for screening who have not fasted

overnight, A1C is the preferred test.• Abnormal results should be confirmed either by repeating

the initial test on another day, or performing a different test.

WHO criteria — The 2006 WHO criteria define diabetes as• a fasting glucose ≥126 mg/dL (7.0 mmol/L) • or a two-hour post glucose challenge value ≥200 mg/dL (11.1 mmol/L).• Impaired glucose tolerance (IGT) is defined as a fasting glucose <126

(7.0 mmol/L), and a two-hour glucose ≥140 mg/dL (7.8 mmol/L) but <200 mg/dL (11.05 mmol/L) .

• Impaired fasting glucose (IFG) is defined as a fasting glucose of 110 to 125 mg/dL (6.1 to 6.9 mmol/L).

• In 2011, the WHO concluded that an A1C value of ≥6.5 percent (48 mmol/mol) can be used as a diagnostic test for diabetes .

• A value of <6.5 percent does not exclude diabetes diagnosed using glucose levels.

• The American Diabetes Association (ADA) issued diagnostic criteria for diabetes mellitus in 1997, with follow-up in 2003 and 2010 .

• The diagnosis is based on one of four abnormalities:• 1. hemoglobin A1C (A1C).• 2. fasting plasma glucose (FPG).• 3. random elevated glucose with symptoms.• 4. or abnormal oral glucose tolerance test (OGTT) .• Patients with impaired fasting glucose (IFG) and/or

impaired glucose tolerance (IGT) are referred to as having increased risk for diabetes .

• Criteria for the diagnosis of diabetes• 1. A1C ≥6.5 percent. The test should be performed in a laboratory using

a method that is NGSP(national glycohemoglobin standardization program) certified and standardized to the DCCT assay(diabetes control and complications trial).*

• OR• 2. FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake

for at least 8 h.*• OR• 3. Two-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT.

The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.*

• OR• 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic

crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L).

• In the absence of unequivocal symptomatic hyperglycemia, the diagnosis of diabetes must be confirmed on a subsequent day by repeat measurement, repeating the same test for confirmation.

• However, if two different tests (eg, FPG and A1C) are available and are concordant for the diagnosis of diabetes, additional testing is not needed.

• If two different tests are discordant, the test that is diagnostic of diabetes should be repeated to confirm the diagnosis .

• Normal —• Fasting plasma glucose (FPG) <100 mg/dL (5.6 mmol/L).

Two-hour glucose during OGTT <140 mg/dL (7.8 mmol/L). Categories of increased risk for diabetes (prediabetes)*• FPG 100-125 mg/dL (5.6-6.9 mmol/L) [IFG]• 2-h PG on the 75-g OGTT 140-199 mg/dL (7.8-11.0 mmol/L)

[IGT]• A1C 5.7-6.4 percent

The adult patient with brittle diabetes mellitus

• Almost all diabetic patients experience swings in blood glucose levels, which are larger and less predictable than in nondiabetics.

• When these swings become intolerable and cause disruption to the person's daily life and/or prolonged hospitalization, the person is labeled as having "labile" or "brittle" diabetes. Although brittle diabetes is uncommon (less than 1 percent of insulin-taking diabetic patients) , it can cause a considerable burden on hospital, social, and family resources due to multiple hospital admissions.

• Most experts would define brittle diabetes as severe instability of blood glucose levels with frequent and unpredictable episodes of hypoglycemia and/or ketoacidosis that disrupt quality of life. Thus, brittle diabetic patients virtually always have type 1 diabetes.

• Three clinical presentations of brittle diabetes have been described: (1) predominant hyperglycemia with recurrent ketoacidosis, (2) predominant hypoglycemia, and (3) mixed hyper- and hypoglycemia .

Complications

• HYPOGLYCEMIA — Hypoglycemia is the most common complication of type 1 diabetes in childhood. Hypoglycemia is usually defined as a blood glucose level <70 mg/dL (3.9 mmol/L) .

• It can occur in whom the dose of administered insulin exceeds insulin requirement.

• Responses to hypoglycemia include release of counterregulatory hormones such as glucagon, epinephrine, cortisol, and growth hormone. However, over time, the glucagon response usually is impaired and the epinephrine surge may be attenuated, increasing the risk of persistent hypoglycemia.

• This is especially likely to occur in tightly controlled patients with frequent biochemical hypoglycemia.

• Symptoms — Hypoglycemic symptoms may be adrenergic due to sympathetic neural activation and epinephrine release , and neuroglycopenic, resulting from direct effects of hypoglycemia on the central nervous system.

• Adrenergic symptoms — Tremor, pallor, rapid heart rate, palpitations, and diaphoresis.

• Neuroglycopenic symptoms — Fatigue, lethargy, headaches, behavior changes, drowsiness, unconsciousness, seizures, or coma.

• The severity of the neuroglycopenic symptoms increases with the severity of hypoglycemia and resultant central nervous system energy deprivation.

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS, also called nonketotic hyperglycemia)

Diabetic ketoacidosis is characteristically associated with type 1 diabetes. It also occurs in type 2 diabetes under conditions of extreme stress such as serious infection, trauma, cardiovascular or other emergencies, and, less often, as a presenting manifestation of type 2 diabetes, a disorder called ketosis-prone diabetes mellitus.

• DKA is more common in young (<65 years) diabetic patients and in women compared to men.

• Mortality in DKA is primarily due to the underlying precipitating illness and only rarely to the metabolic complications of hyperglycemia or ketoacidosis .

• the rate of hospital admissions for HHS is lower than the rate for DKA, and accounts for less than 1 percent of all primary diabetic admissions .

HHS is most commonly seen in individuals older than 65 years with type 2 diabetes . Mortality attributed to HHS is higher than that of DKA, with rates ranging from 5 to 20 percent; as in DKA, mortality is most often due to the underlying illness or comorbidity .

• Precipitating factors — Both DKA and HHS are usually precipitated by stresses .• Infection- • pneumonia, • gastroenteritis, • and urinary tract infection, can be found in 40 to 50 percent of patients with

hyperglycemic crisis; • other stresses include pancreatitis, • myocardial infarction, • stroke, trauma, • and alcohol and drug abuse.• The serum glucose concentration in HHS frequently exceeds 1000 mg/dL (56

mmol/L), but in DKA is generally below 800 mg/dL (44 mmol/L) .

Ketoacidosis• Acetoacetic acid is the initial ketone formed; it may then be reduced to beta-

hydroxybutyric acid, which is also an organic acid, or nonenzymatically decarboxylated to acetone, which is chemically neutral .

• Ketones provide an alternate source of energy when glucose utilization is impaired.

• Insulin deficiency and increased catecholamine lead to enhanced lipolysis, thereby increasing free fatty acid delivery to the liver .

• Normal subjects will convert these free fatty acids primarily into triglycerides.

• The development of ketoacidosis requires a specific alteration in hepatic metabolism so that free fatty acyl CoA can enter the mitochondria, where conversion to ketones occurs.

• In states of insulin deficiency, the combination of increased free fatty acid delivery and glucagon excess promotes ketogenesis.

CLINICAL PRESENTATION —• DKA usually evolves rapidly, over a 24-hour period. • In contrast, symptoms of HHS develop more insidiously with polyuria,

polydipsia, and weight loss, often persisting for several days before hospital admission.

• As the degree or duration of hyperglycemia progresses, neurologic symptoms, including lethargy, focal signs, and obtundation, which can progress to coma in later stages, can be seen.

• Neurological symptoms are most common in HHS, while hyperventilation and abdominal pain are primarily limited to patients with DKA.

• Initial evaluation —• Both DKA and HHS are medical emergencies that require

prompt recognition and management.• An initial history and rapid but careful physical examination

should focus on:• -Airway, breathing, and circulation (ABC) status• -Mental status• -Possible precipitating events (eg, source of infection,

myocardial infarction)• -Volume status

• Neurologic symptoms and plasma osmolality — • Neurologic deterioration primarily occurs in patients with an effective

plasma osmolality above 320 to 330 mosmol/kg . Mental obtundation and coma are more frequent in HHS than DKA because of the usually greater degree of hyperosmolality in HHS .

• The effective plasma osmolality (Posm, in mosmol/kg) can be estimated from either of the following equations:

• Effective Posm = [2 x Na (meq/L)] + [glucose (mg/dL) ÷ 18]• Effective Posm = Measured Posm - [BUN (mg/dL) ÷ 28]• Where Na is the serum sodium concentration, the multiple 2 accounts for the

osmotic contribution of the anions accompanying sodium (primarily chloride and bicarbonate), and 18 and 28 are conversion factors from units of mg/dL into mmol/L.

• Where standard units are used, the following equations apply:• Effective Posm = [2 x Na (mmol/L)] + glucose (mmol/L)• Effective Posm = Measured Posm - BUN or blood urea (mmol/L)

• Physical examination — • Signs of volume depletion are common in both DKA and

HHS, including decreased skin turgor, dry axillae and oral mucosa, low jugular venous pressure and, if severe, hypotension.

• Patients with DKA may have a fruity odor (due to exhaled acetone and similar to the odor of nail polish remover), and deep respirations reflecting the compensatory hyperventilation (called Kussmaul respirations).

• Fever is rare even in the presence of infection, because of peripheral vasoconstriction due to hypovolemia.

LABORATORY FINDINGS —

• The initial laboratory evaluation of a patient with suspected DKA or HHS should include determination of:

• Serum glucose• Serum electrolytes (with calculation of the anion gap), BUN, and serum

creatinine• Complete blood count with differential• Urinalysis, and urine ketones by dipstick• Plasma osmolality• Serum ketones (if urine ketones are present)• Arterial blood gas (if urine ketones or anion gap are present)• Electrocardiogram• Additional testing, such as cultures of urine, sputum, and blood, serum lipase

and amylase, and chest x-ray, should be performed on a case-by-case basis

DKAHHS

MildModerateSevere

Plasma glucose (mg/dL)>250>250>250>600

Arterial pH7.25-2.30

7.00-7.24<7.00>7.30

Serum bicarbonate (mEq/L)15-1810 to <15<10>18

Urine ketonespositivepositivepositivesmall

Serum ketonesPositivepositivepositivesmall

Effective serum osmolality (mOsm/kg)•

VariableVariableVariable>320

Anion gapΔ>10>12>12Variable

Alteration in sensoria or mental obtundation

AlertAlert/drowsyStupor/comaStupor/coma

TREATMENT

• Stabilize the patient's airway, breathing, and circulation.• Obtain large bore IV (≥16 gauge) access; monitor using a cardiac monitor,

capnography, and pulse oximetry.• Monitor serum glucose hourly, and basic electrolytes, plasma osmolality, and

venous pH every two to four hours until the patient is stable.• Determine and treat any underlying cause of DKA (eg, pneumonia or urinary

infection, myocardial ischemia).• Replete fluid deficits:• Give several liters of isotonic (0.9 percent) saline as rapidly as possible to patients

with signs of shock. • • Give isotonic saline at 15 to 20 mL/kg per hour, in the absence of cardiac

compromise, for the first few hours to hypovolemic patients without shock. • • After intravascular volume is restored, give one-half isotonic (0.45 percent) saline

at 4 to 14 mL/kg per hour if the corrected serum sodium is normal or elevated; isotonic saline is continued if the corrected serum sodium is reduced.

• • Add dextrose to the saline solution when the serum glucose reaches 200 mg/dL (11.1 mmol/L).

• Replete potassium (K+) deficits:

• • If initial serum K+ is below 3.3 mEq/L, hold insulin and give K+ 20 to 30 mEq/hour IV until K+ concentration is above 3.3 mEq/L.

• • If initial serum K+ is between 3.3 and 5.3 mEq/L, give K+ 20 to 30 mEq per liter IV fluid; maintain K+ between 4 to 5 mEq/L.

• • If initial serum K+ is above 5.3 mEq/L do not give K+; check K+ every 2 hours. Give insulin:

• • Do not give insulin if initial serum K+ is below 3.3 mEq/L; replete K+ first.• • Give all patients without a serum K+ below 3.3 mEq/L regular insulin. Either of two

regimens can be used: 0.1 units/kg IV bolus, then start a continuous IV infusion 0.1 units/kg per hour;

• OR do not give bolus and start a continuous IV infusion at a rate of 0.14 units/kg per hour.

• • Continue insulin infusion until ketoacidosis is resolved, serum glucose is below 200 mg/dL (11.1 mmol/L), and subcutaneous insulin is begun.

• Give sodium bicarbonate to patients with pH below 7.00:• • If the arterial pH is between 6.90 and 7.00, give 50 meq of sodium bicarbonate plus

10 meq of potassium chloride in 200 mL of sterile water over two hours. • • If the arterial pH is below 6.90, give 100 meq of sodium bicarbonate plus 20 meq of

potassium chloride in 400 mL sterile water over two hours.

• Microvascular complications — • Microvascular complications of diabetes include :• Retinopathy.• Nephropathy.• and neuropathy (peripheral and autonomic). • 20 percent of diagnosed with type 2 diabetes before 20

years of age developed nephropathy over 25 years . This incidence was not different from those with adult-onset type 2 diabetes.

• Nephropathy — Diabetes-associated nephropathy is a progressive disorder of the microvasculature of the kidney.

• Microalbuminuria, defined as persistent albumin excretion between 30 and 300 mg/day (20 to 200 mcg/min), is the earliest stage of nephropathy.

• In youth with diabetes, microalbuminuria predicts progression of nephropathy to overt proteinuria [albumin excretion >300 mg/day (200 mcg/min)], which can be accompanied by systemic hypertension and impaired glomerular filtration .

• Some patients with overt proteinuria will progress to end-stage renal disease.

• Treatment for microalbuminuria includes optimization of glycemic control and the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers.

Retinopathy SCREENING—Type 1 diabetesWithin 5 years after diagnosis of diabetes once patient is

age 10 years or older-then Yearly.• Type 2 diabetesAt time of diagnosis of diabetes.then Yearly.• Classification-• Background retinopathy describes the earliest retinal changes including

dilated retinal venules, microaneurysms, and capillary leakage (picture 1). Loss of visual acuity can occur if these changes are near the macula.

• Preproliferative retinopathy is the second stage of retinopathy with retinal microinfarcts visible as small flame-shaped blot hemorrhages proximal to the occlusion (picture 2) and "cotton wool" or "soft exudates" distal to the occlusion (picture 3).

• Proliferative retinopathy is the most severe form. It includes retinal ischemia, proliferation of new retinal blood vessels (picture 4), further hemorrhage, scarring resulting from contraction of fibrovascular proliferation, and retinal detachment.

•Background diabetic retinopathy showing microaneurysms (small arrows) and hard exudates. The blood vessels can be seen running over the hard exudates (large arrow), indicating that the exudates are due to leakage in the deeper retinal layers (in contrast to soft exudates, which are microinfarcts in the superficial retinal layers with obliterated blood vessels). Many of the hard exudates are clustered around the macula, which is at the periphery at about four o'clock.

• Diabetic retinopathy, showing several blot hemorrhages (arrows). These lesions are due to vascular occlusion and rupture.

• Cotton wool spots are indicative of retinal ischemia. The differential diagnosis includes diabetes, hypertension, AIDS, and the retinal vascular changes of systemic lupus erythematosus.

• Diabetic retinopathy, showing irregular changes in venous caliber, tortuosity of blood vessels, and proliferation of networks of fragile new vessels, arising from both arteries and veins (arrows).

• Neuropathy —• Involvement of the peripheral and autonomic nervous systems is

probably the most common complication of diabetes. • CLASSIFICATION —• Diabetic neuropathy is classified into distinct clinical syndromes. A

characteristic set of symptoms and signs exist for each syndrome, depending on the component of the peripheral nervous system that is affected.

• The most frequently encountered neuropathies include :• Distal symmetric polyneuropathy• Autonomic neuropathy• Thoracic and lumbar nerve root disease, causing polyradiculopathies• Individual cranial and peripheral nerve involvement causing focal

mononeuropathies, especially affecting the oculomotor nerve (cranial nerve III) and the median nerve

• Asymmetric involvement of multiple peripheral nerves, resulting in a mononeuropathy multiplex

• Cardiovascular disease• Heart disease, particularly coronary heart disease (CHD) is a

major cause of morbidity and mortality among patients with diabetes mellitus .

• Compared to individuals without diabetes, those with diabetes have a higher prevalence of

• CHD.• a greater extent of coronary ischemia.• and are more likely to have a myocardial infarction (MI).• and silent myocardial ischemia.

SystemSymptoms

CardiovascularPostural hypotensionPostprandial hypotensionFixed tachycardiaFoot complicationsSudden cardiac death

GastrointestinalEsophageal motility disordersGastroparesisConstipation, diarrhea, incontinence

GenitourinaryBladder dysfunctionSexual dysfunction

SudomotorDistal anhidrosisGustatory sweating

Abnormal pupillary responsesfailure in dark adaptation and difficulties in night driving

Neuroendocrine responses to hypoglycemiaReduced glucagon secretionDelayed epinephrine secretion

Evaluation of the diabetic foot• Foot problems are an important cause of morbidity in

patients with diabetes mellitus.• PHYSICAL EXAMINATION — The physical examination should

include an assessment for• the presence of existing ulcers,• peripheral neuropathy (loss of protective sensation [LOPS]), • peripheral artery disease, • and foot deformities that may predispose the patient to the

development of foot ulcers .• Several reports indicate that adequate examinations

relevant to foot ulceration are often not performed in diabetic patients.

• Advice for prophylactic foot care should be given to all patients :

• Avoid going barefoot, even in the home.• Test water temperature before stepping into a bath.• Trim toenails to shape of the toe; remove sharp edges with a

nail file. Do not cut cuticles.• Wash and check feet daily.• Shoes should be snug but not tight and customized if feet

are misshapen or have ulcers.• Socks should fit and be changed daily.

management of blood glucose in type 2 diabetes mellitus

• Treatment of patients with type 2 diabetes mellitus includes• education, • evaluation for microvascular and macrovascular complications, • normalization of glycemia, • minimization of cardiovascular and other long-term risk factors, • and avoidance of drugs that can aggravate abnormalities of insulin or lipid

metabolism.• TREATMENT GOALS• Degree of glycemic control — Achieving near normal blood glucose concentrations

markedly reduces the risk of microvascular and macrovascular complications in type 1 diabetes.

• Improved glycemic control also improves the risk of microvascular complications in patients with type 2 diabetes .

• Every 1 percent drop in A1C is associated with improved outcomes with no threshold effect.

• To date, no randomized clinical trial has convincingly demonstrated a beneficial effect of intensive therapy on macrovascular outcomes in type 2 diabetes.

• Nonpharmacologic therapy in type 2 diabetes —• There are three major components to nonpharmacologic therapy of blood

glucose in type 2 diabetes :• Dietary modification• Exercise• Weight reduction• In addition to improving glycemic control, these changes in lifestyle also slow

progression of impaired glucose tolerance to overt diabetes . • Diet and exercise are important components of therapy in patients with type

1 diabetes. • Surgical treatment of obese patients with diabetes results in the largest

degree of sustained weight loss and, in parallel, the largest improvements in blood glucose control. Pharmacotherapy for weight loss may also be used for patients with type 2 diabetes, but may not be effectively sustained due to side effects.

• Pharmacologic therapy for diabetes • — The American Diabetes Association (ADA) and the European Association

for the Study of Diabetes (EASD) issued a 2006 consensus statement for the management of glycemia in type 2 diabetes, which was updated in 2009 .

• Because of the difficulty in achieving and sustaining goal glycemia and significant weight loss, the consensus group concluded that metformin therapy should be initiated concurrent with lifestyle intervention at the time of diagnosis.

• The therapeutic options for patients who fail initial therapy with lifestyle intervention and metformin are to add a second oral or injectable agent, including insulin, or to switch to insulin .

• Type 2 diabetic patients often need large daily doses of insulin (>65 units per day, and often much more) to achieve acceptable glycemic control.

• Most patients with type 2 diabetes can be treated with one or two daily injections, in contrast to patients with type 1 diabetes for whom intensive insulin therapy with multiple daily injections is indicated.

• In patients with contraindications to metformin, a shorter acting sulfonylurea, such as glipizide.

• Insulin is also a reasonable option for initial therapy in patients who present with symptomatic or poorly controlled diabetes or in patients in whom it is difficult to distinguish type 1 from type 2 diabetes.

• In patients who are intolerant of or are not candidates for metformin or sulfonylureas, repaglinide is a reasonable alternative, particularly in a patient with chronic kidney disease at risk for hypoglycemia.

• Pioglitazone may also be considered in patients with specific contraindications to metformin and sulfonylureas.

• However, the risk of heart failure, fractures, and the potential increased risk of bladder cancer raises the concern that the overall risks and cost of pioglitazone may exceed its benefits.

• Sulfonylureas can be effective when used as monotherapy, or in combination with other oral hypoglycemic drugs or insulin.

• Sulfonylureas usually lower blood glucose concentrations by about 20 percent and A1C by 1 to 2 percent .

• They are most likely to be effective in patients whose weight is normal or slightly increased. In contrast, insulin should be used in patients (regardless of age) who are underweight, are losing weight, or are ketotic despite adequate caloric intake.

• A typical initial sulfonylurea regimen consists of 2.5 mg of glipizide taken 30 minutes before breakfast. If adequate glycemic control is not attained in the next two to four weeks, the dose can be increased to 5 mg and then 10 mg, given before breakfast or before breakfast and the evening meal. The maximum dose of glipizide can be up to 40 mg/day. However, these maximum doses rarely improve glycemic control, and higher doses should generally be avoided .

• Other, infrequent side effects that can occur with all sulfonylureas include nausea, skin reactions (including photosensitivity), and abnormal liver function tests. Chlorpropamide has two unique effects: it can cause an unpleasant flushing reaction after alcohol ingestion by inhibiting the metabolism of acetaldehyde ; and it can cause hyponatremia, primarily by increasing the action of vasopressin

• MEGLITINIDES — • The meglitinides, repaglinide and nateglinide, are short-acting glucose-lowering drugs

for therapy of patients with type 2 diabetes alone or in combination with metformin.• Thiazolidinediones• The thiazolidinediones, rosiglitazone and pioglitazone, lower blood glucose

concentrations by increasing insulin sensitivity.• DPP-IV inhibitors —Dipeptidyl peptidase IV (DPP-IV) , Sitagliptin and saxagliptin• is a ubiquitous enzyme that deactivates a variety of other bioactive peptides,

including glucagon-like peptide-1 and gastric inhibitory peptide; therefore, its inhibition could potentially affect glucose regulation through multiple effects.

• Glucagon-like peptide 1 agonists — Exenatide and liraglutide are glucagon-like peptide 1 (GLP-1) analogs that are administered subcutaneously. They are approved in the United States by the FDA for the treatment of type 2 diabetes in patients not sufficiently controlled with diet, exercise, or oral agents

• Alpha-glucosidase inhibitors —The alpha-glucosidase inhibitors (acarbose, miglitol, voglibose) have been studied extensively .

• Taken orally, they inhibit the upper gastrointestinal enzymes (alpha-glucosidases) that convert complex polysaccharide carbohydrates into monosaccharides in a dose-dependent fashion.

General principles of insulin therapy in diabetes mellitus

• Insulin is used in the treatment of patients with diabetes of all types.

• The need for insulin depends upon the balance between insulin secretion and insulin resistance.

• All patients with type 1 diabetes need insulin treatment permanently, unless they receive an islet or whole organ pancreas transplant;

• many patients with type 2 diabetes will require insulin as their beta cell function declines over time.

• In healthy individuals a sharp increase in insulin occurs after meals; this is superimposed on a constant background of secretion.

• Insulin therapy attempts to reproduce this pattern, but ideal control is difficult to achieve for four reasons:

1. In normal subjects, insulin is secreted directly into the portal circulation and reaches the liver in high concentration; about 50% of the insulin produced by the pancreas is cleared by the liver. By contrast, insulin injected subcutaneously passes into the systemic circulation before passage to the liver. Insulin-treated patients therefore have lower portal levels of insulin and higher systemic levels relative to the physiological situation.

2. Subcutaneous soluble insulin takes 60-90 minutes to achieve peak plasma levels, so the onset and offset of action are too slow.

3. The absorption of subcutaneous insulin into the circulation is variable.4. Basal insulin levels are constant in normal people, but injected insulin

invariably peaks and declines in people with diabetes, with resulting swings in metabolic control.

Insulin PreparationsClassAgents

Human insulinsRegular, NPH, lente, ultralente

Insulin analoguesAspart, glulisine, lispro, glargine

Premixed insulinsHuman 70/30, 50/50Humalog mix 75/25Novolog mix 70/30

• A multiple injection regimen with short-acting insulin and a longer-acting insulin at night is appropriate for most younger patients.

• The advantages of multiple injection regimens are that the insulin and the food go in at roughly the same time so that meal times and sizes can vary, without greatly disturbing metabolic control.

Duration of Action of Standard Insulins and Insulin Analogues

InsulinOnset of ActionPeak of ActionEffective Duration

Standard

Regular30-60 min2-3 h8-10 h

NPH2-4 h4-10 h12-18 h

Zinc Insulin(Lente)2-4 h4-12 h12-20 h

Extended Zinc Insulin(Ultralente)

6-10 h10-16 h18-24 h

Analogues

Lispro5-15 min30-90 min4-6 h

Aspart5-15 min30-90 min4-6 h

Glargine2-4 hNone20-24 h

The Basal-Bolus Insulin Concept

Basal insulin• Controls glucose production between meals and overnight• Nearly constant levels • 50% of daily needs

Bolus insulin (mealtime or prandial)• Limits hyperglycemia after meals• Immediate rise and sharp peak at 1 hour postmeal • 10% to 20% of total daily insulin requirement at each meal

For ideal insulin replacement therapy, each component should come from a different insulin with a specific profile.

Barriers to Using Insulin

• Patient resistance– Perceived significance of needing insulin– Fear of injections– Complexity of regimens– Pain, lipohypertrophy

• Physician resistance– Perceived cardiovascular risks– Lack of time and resources to supervise treatment

• Medical limitations of insulin treatment– Hypoglycemia– Weight gain

Insulin Injection Devices

• Insulin pens

• Faster and easier than syringes

– Improve patient attitude and adherence

– Have accurate dosing mechanisms, but inadequate mixing may be a problem

Insulin Pumps

•Continuous subcutaneous insulin infusion (CSII) – External, programmable pump connected

to an indwelling subcutaneous catheter to deliver rapid-acting insulin

•Intraperitoneal insulin infusion– Implanted, programmable

pump with intraperitoneal catheter. Not available in the United States

New Insulins in Clinical Development

• Long-acting insulin analogue – Insulin detemir– Acylated insulin analogue– Soluble, binds to albumin

• Rapid-acting insulin analogue – Insulin 1964– Limited aggregation, like lispro and aspart– Rapid absorption from injection site

• Inhaled insulins – Aerodose, AERx, Exubera

– Liquid aerosol or particulate cloud– Delivered by portable devices

• Buccally absorbed insulin – Oralin

– Liquid aerosol – Delivered by portable device

D.Dx of Early Morning Hyperglycemia

Somogi Effect :• High sugar in early morning due to rebound response to

hypoglycemia at 2-3 AM, treatment is by decreasing evening NPH dose.

Down phenomenon :• High sugar in early morning due to physiologic release of

GH and ACTH at early morning hours

Guide to adjusting insulin dosage according to blood glucose test results

Blood glucose persistently too high

Blood glucose persistently too low

Before breakfastIncrease evening long-acting insulin

Reduce evening long-acting insulin

Before lunchIncrease morning short-acting insulin

Reduce morning short-acting insulin or increase mid-morning snack

Before evening mealIncrease morning long-acting insulin or lunch short-acting insulin

Reduce morning long-acting insulin or lunch short-acting insulin or increase mid-afternoon snack

Before bedIncrease evening short-acting insulin

Reduce evening short-acting insulin