Diabetes Mellitus

የህዝብ በህዝብ ለህዝብ

Abyot
Harrison and DR Ahmed handout
2015
 DM is the leading cause of end-stage renal disease (ESRD), nontraumatic lower extremity
amputations, and adult blindness.
Etiologic Classification of DM

 Type 1
– Autoimmune – Type 1A
– Idiopathic – Type 1B
 Type 2
– Predominantly Insulin Resistance
– Predominantly Insulin Secretory Defects
 Other Specific Types
 Gestational Diabetes Mellitus
Other Specific Types Of Diabetes
Other Specific Types Of Diabetes
1. Genetic Defect Of Beta Cells e.g. MODY
2. Genetic Defects In Insulin Action e.g. Type A Insulin
Resistance
3. Diseases Of The Exocrine Pancreas e.g. FCPP, Tumors ,
pancreatitis, pancreatectomy,cystic fibrosis
4. Endocrinopathies e.g. Acromegaly, Cushing's syndrome,
glucagonoma
5. Drug- Or Chemical Induced e.g. Steroids
6. Infections e.g. Congenital Rubella, CMV
7. Rare Immune-mediated Diabetes e.g. "Stiff-man" Syndrome
8. Other Genetic Syndromes e.g. Down's Syndrome , anti-insulin
receptor antibodies
CONT’D

 Maturity-onset diabetes of the young (MODY) is a subtype of DM characterized by

autosomal dominant inheritance, early onset of hyperglycemia (usually <25 years), and
impairment in insulin secretion.
 Hormones that antagonize insulin action can also lead to DM. Thus, DM is often a feature
of endocrinopathies such as acromegaly and Cushing's disease.
Gestational Diabetes Mellitus (GDM)
Gestational Diabetes Mellitus (GDM)

 Glucose intolerance developing during pregnancy is classified as gestational diabetes.

Insulin resistance is related to the metabolic changes of late pregnancy, and the
increased insulin requirements may lead to IGT or diabetes.
 GDM occurs in 7% (range 2–10%) of pregnancies in the United States; most women
revert to normal glucose tolerance postpartum but have a substantial risk (35–60%) of
developing DM in the next 10–20 years.
 It is recommended that diabetes diagnosed at the initial prenatal visit should be classified
as "overt" diabetes rather than gestational diabetes.
Epidemiology

 Although the prevalence of both type 1 and type 2 DM is increasing worldwide, the
prevalence of type 2 DM is rising much more rapidly, presumably because of increasing
obesity, reduced activity levels as countries become more industrialized, and the aging of
the population
 DM increases with aging
 The prevalence is similar in men and women throughout most age ranges
Reasons for Explosive Rise in Diabetes
& NCDs
 Aging Populations
 Epidemiological Transition
 Obesity
 Harmful Lifestyles
– Physical Inactivity
– Unhealthy Diet
– Smoking
– Alcohol Abuse
 Harmful Environments
– Unplanned Urbanization & Globalization
– Rapid & Unregulated Economic Transformation
 There is considerable geographic variation in the incidence of both type 1 and type 2 DM.
Scandinavia has the highest incidence of type 1 DM.
 A recent estimate suggested that diabetes was the fifth leading cause of death
worldwide.
Diagnosis of DM
Diagnosis of Diabetes
Diagnosis A1C Fasting Random 2-hour
% Glucose Glucose* 75g OGTT
mg/dL mg/dL mg/dL

Normal < 5.6% < 100 - < 140

Prediabetes 5.7– 100– - 140–199

6.4% 125
Diabetes > 6.5 % > 126 > 200 + > 200
symptoms
* Random glucose cannot be used to diagnose prediabetes
 Random is defined as without regard to time since the last meal.
 Fasting is defined as no caloric intake for at least 8 hr.
 Oral glucose tolerance test: blood glucose is measured after ingestion of 75g anhydrous
of glucose dissolved in water.
 In the absence of unequivocal hyperglycemia and acute metabolic decompensation,
these criteria should be confirmed by repeat testing on a different day
 The current criteria for the diagnosis of DM emphasize that the A1C or the FPG as the
most reliable and convenient tests for identifying DM in asymptomatic individuals.
 The diagnosis of DM has profound implications for an individual from both a medical and
a financial standpoint. Thus, abnormalities on screening tests for diabetes should be
repeated before making a definitive diagnosis of DM.
Screening

 Widespread use of the FPG or the A1C as a screening test for type 2 DM is recommended
because
1. A large number of individuals who meet the current criteria for DM are asymptomatic and
unaware that they have the disorder,
2. Epidemiologic studies suggest that type 2 DM may be present for up to a decade before
diagnosis
3. Some individuals with type 2 DM have one or more diabetes-specific complications at the
time of their diagnosis, and
4. Treatment of type 2 DM may favorably alter the natural history of DM.
 The ADA recommends screening all individuals
 >45 years every 3 years
 BMI >25 kg/m2 and
 Have one additional risk factor for diabetes (next slide). In contrast to type 2 DM, a long
asymptomatic period of hyperglycemia is rare prior to the diagnosis of type 1 DM.
Risk Factors for Type 2 Diabetes Mellitus

Family history of diabetes (i.e., parent or sibling with type 2 diabetes)

Obesity (BMI >25 kg/m2)

Physical inactivity
Race/ethnicity (e.g., African American, Latino, Native American)
Previously identified with IFG, IGT, or an A1C of 5.7–6.4%
History of GDM or delivery of baby >4 kg
Hypertension (blood pressure >140/90 mmHg)
HDL cholesterol level <35 mg/dL and/or triglyceride level >250 mg/dL
Polycystic ovary syndrome or acanthosis nigricans
History of cardiovascular disease
Insulin Biosynthesis

 Insulin is produced in the beta cells of the pancreatic islet. A,B,C peptides
 Because C peptide is cleared more slowly than insulin, it is a useful marker of insulin
secretion.
Secretion

 Glucose is the key regulator of insulin secretion by the pancreatic beta cell, although
amino acids, ketones, various nutrients, gastrointestinal peptides, and neurotransmitters
also influence insulin secretion. Glucose levels >70 mg/dL stimulate insulin synthesis.
 Glucose stimulation of insulin secretion begins with its transport into the beta cell by a
facilitative glucose transporter.
Cont’d

 Glucose phosphorylation by glucokinase is the rate-limiting step. Further metabolism of

glucose-6-phosphate via glycolysis generates ATP, which inhibits the activity of an ATP-
sensitive K+ channel. Inhibition of this K+ channel induces beta cell membrane
depolarization, which opens voltage-dependent calcium channels (leading to an influx of
calcium), and stimulates insulin secretion.
Cont’d

 Incretins are released from neuroendocrine cells of the gastrointestinal tract following
food ingestion and amplify glucose-stimulated insulin
 Secretion and suppress glucagon secretion. Glucagon-like peptide 1 (GLP-1), the most
potent incretin, is released from L cells in the small intestine and stimulates insulin
secretion only when the blood glucose is above the fasting level.
 Incretin analogues, are used to enhance endogenous insulin secretion.
Action

 Once insulin is secreted into the portal venous system, 50% is removed and degraded by
the liver. Unextracted insulin enters the systemic circulation where it binds to receptors
in target sites.
 Glucose uptake by skeletal muscle and fat, glycogen synthesis, protein synthesis,
lipogenesis.
Cont’d

 Glucagon, secreted by pancreatic alpha cells when blood glucose or insulin levels are low,
stimulates glycogenolysis and gluconeogenesis by the liver and renal medulla.
Postprandially, the glucose load elicits a rise in insulin and fall in glucagon.
 The major portion of postprandial glucose is utilized by skeletal muscle, an effect of
insulin-stimulated glucose uptake.
 Other tissues, most notably the brain, utilize glucose in an insulin-independent fashion
Type 1 DM
Type 1 DM

 Type 1 DM is the result of interactions of genetic, environmental, and immunologic

factors that ultimately lead to the destruction of the pancreatic beta cells and insulin
deficiency. Type 1 DM results from autoimmune beta cell destruction, and most, but not
all, individuals have evidence of islet-directed autoimmunity.
 Individuals with a genetic susceptibility have normal beta cell mass at birth but begin to
lose beta cells secondary to autoimmune destruction that occurs over months to years.
This autoimmune process is thought to be triggered by an infectious or environmental
stimulus and to be sustained by a beta cell–specific molecule.
 Beta cell mass then begins to decrease, and insulin secretion progressively declines,
although normal glucose tolerance is maintained.
 Features of diabetes do not become evident until a majority of beta cells are destroyed
(70–80%).
 At this point, residual functional beta cells exist but are insufficient in number to maintain
glucose tolerance. The events that trigger the transition from glucose intolerance to frank
diabetes are often associated with increased insulin requirements, as might occur during
infections or puberty.
 After the initial clinical presentation of type 1 DM, a "honeymoon" phase may ensue
during which time glycemic control is achieved with modest doses of insulin or, rarely,
insulin is not needed. However, this fleeting phase of endogenous insulin production
from residual beta cells disappears as the autoimmune process destroys remaining beta
cells, and the individual becomes insulin deficient
 Genetic Considerations
 The concordance of type 1 DM in identical twins ranges between 40 and 60%, indicating
that additional modifying factors are likely involved in determining whether diabetes
develops. The major susceptibility gene for type 1 DM is located in the HLA region on
chromosome 6.
Type 1

 They require insulin for survival and develop ketoacidosis when patients are not on
adequate insulin therapy.
 Accounts for 10% of cases of DM.
 Oral hypoglycemic agents will not be effective to lower the blood glucose level.
 Type 1 DM is due to β-cell destruction, with absolute deficiency of insulin, which is of
multifactorial causes such as genetic predisposition, viral and autoimmune attacks on the
beta islet cells.
 It may be immune mediated or idiopathic.
Type 1A Diabetes Mellitus
 Cellular Mediated Autoimmune Destruction Of Beta Cells

 Markers Of Autoimmunity: ICA, IAA, Anti GAD Antibodies

 Strong HLA Association

 Variable Rate Of Beta Cell Destruction

Type 1A Diabetes Mellitus (Cont’d)

 Acute Onset And Profound Symptoms

 Age < 30 Years (Neonate – 80+)
 Non-obese (Obesity Not Incompatible)
 Ketonuria &/or Metabolic Acidosis
 Immediate & Permanent Need For Insulin
 No Microvascular Complications at Diagnosis
 Prone to Other Autoimmune Diseases: Graves’,
Hashimoto’s, Addison’s Diseases, etc.
Type 1B Diabetes Mellitus
 Young Patients
 Abrupt Onset (Mean Duration Of Symptoms – 4 Days)
 Prone To DKA Soon After Onset
 No Insulitis on Biopsy/Autopsy
 No Hyper-expression Of MHC Class I Molecules In Islets
 No Diabetes-related Antibodies
 Highly Elevated Serum Pancreatic Enzymes
 Lymphocytic Infiltration Of The Exocrine Pancreas
 No Classic Features of Acute/Chronic Pancreatitis
 Type 1 diabetes mellitus is believed to be due to autoimmune destruction of beta cells.
 The triggering agent (i.e. - a viral infection) will expose these cryptic (hidden) self antigens
to which the immune system has not developed tolerance. Therefore an autoimmune
process is set-up destroying self tissue, in this case the beta cells of the islets of
Langerhans.
 The other mechanism of injury is molecular mimicry between trigger antigen (virus) and
β-cell antigen. or instance Coxsackie virus antigen and that of glutamic acid
decarboxylase (GAD) found within the β-cells has similar chemical structure, so that the
antibodies produced to fight the foreign antigen of the virus also cross react with
antigens of self tissue bearing GAD hence destroying it .
 Honeymoon period:
 In young people who are diagnosed for the first time to have overt DM, the DM may have
been precipitated by acute metabolic stressful conditions (such as infection or
pregnancy). In such circumstances, the increased metabolic demand for insulin, may lead
to a relative insulin deficiency, and patients become symptomatic, and may need
exogenous insulin to control their symptoms.
 With the return to baseline metabolic demands, when the stressful event abates, the
pancreatic reserve may be adequate to maintain normal or near-normal blood glucose.
Such patients may undergo a period of transient “cure” during which time they may not
require exogenous Insulin to control their blood glucose level. Because of this, such
patients are said to be in a “HONEYMOON” period.
 Studies of the autoimmune process in type 1 DM have identified:
 (1) islet cell autoantibodies; (2) activated lymphocytes in the islets, peripancreatic
lymph nodes, and systemic circulation; (3) T lymphocytes that proliferate when
stimulated with islet proteins; and (4) release of cytokines within the insulitis.
 The islet destruction is mediated by T lymphocytes rather than islet autoantibodies,
 Immunologic Markers
 Testing for ICAs (Islet cell autoantibodies)can be useful in classifying the type of DM as
type 1.
 ICAs are present in individuals of >85% diagnosed with new-onset type 1 DM, in a
significant minority of individuals with newly diagnosed type 2 DM (5–10%), and
occasionally in individuals with GDM (<5%).
Type 2 DM
Type 2 DM

 Insulin resistance and abnormal insulin secretion are central to the development of type
2 DM.
Type 2 Diabetes Mellitus
 Relative Insulin Deficiency
 intact beta islet cell function but there
is peripheral tissue resistance to
insulin.
 Patients do not require insulin for
survival at least in the earlier phase of
diagnosis.
 The blood sugar level can be corrected
by oral hypoglycemic agents.
 In type 2 DM, insulin resistance is often associated with abdominal obesity (as opposed
to hip and thigh obesity) and hypertriglyceridemia.
 Symptomatic/Asymptomatic
 Age > 40 Years
 Positive Family History
 A low C-peptide level confirms a patient's need for insulin.
 Measurement of islet cell antibodies at the time of diabetes onset may be useful if the
type of DM is not clear based on the characteristics
 Cont’d
 Hyperosmolar Hyperglycemic State,
DKA Very Rarely
 Risk Increases With Age, Obesity,
Sedentary Life Style, Prior GDM
 Microvascular Complications May Be
Present at Diagnosis
 Major Morbidity & Mortality From
Macrovascular Disease
 More Frequent In Persons With HPN &
Dyslipidemias
 Natural history of type 2 diabetes
 Stage 1: Insulin resistance: increased glucose and Non Esterified Fatty Acids (NEFA)
 Stage 2: Increased insulin secretion: compensatory hyperinsulinemia
 Stage 3: Impaired glucose tolerance
 Stage 4: Overt type 2 diabetes
 Genetic Considerations
 Type 2 DM has a strong genetic component. The disease is polygenic and multifactorial,
since in addition to genetic susceptibility, environmental factors (such as obesity,
nutrition, and physical activity) modulate the phenotype.
 Pathophysiology
 Type 2 DM is characterized by impaired insulin secretion, insulin resistance, excessive
hepatic glucose production, and abnormal fat metabolism. Obesity, particularly visceral
or central (as evidenced by the hip-waist ratio), is very common in type 2 DM (80% or
more are obese.
 Abnormal Muscle and Fat Metabolism
 Insulin resistance, the decreased ability of insulin to act effectively on target tissues
(especially muscle, liver, and fat), is a prominent feature of type 2 DM and results from a
combination of genetic susceptibility and obesity. Insulin resistance is relative, however,
since supranormal levels of circulating insulin will normalize the plasma glucose.
 Increased hepatic glucose output predominantly accounts for increased FPG levels,
whereas decreased peripheral glucose usage results in postprandial hyperglycemia.
 Glucose metabolism in insulin-independent tissues is not altered in type 2 DM.
 The increased production of free fatty acids and some adipokines may cause insulin
resistance in skeletal muscle and liver.
 Adipocyte products and adipokines also produce an inflammatory state and may explain
why markers of inflammation such as IL-6 and C-reactive protein are often elevated in
type 2 DM.
 Impaired Insulin Secretion
 In type 2 DM, insulin secretion initially increases in response to insulin resistance to
maintain normal glucose tolerance.
 Beta cell mass is decreased by approximately 50% in individuals with long-standing type 2
diabetes.
 Amyloid fibrillar deposit found in the islets of individuals with long-standing type 2 DM.
 Increased Hepatic Glucose and Lipid Production
 As a result of insulin resistance in adipose tissue, lipolysis and free fatty acid flux from
adipocytes are increased, leading to increased lipid [very low density lipoprotein (VLDL)
and triglyceride] synthesis in hepatocytes. This leads to nonalcoholic fatty liver disease
and abnormal liver function tests.
 This is also responsible for the dyslipidemia found in type 2 DM [elevated triglycerides,
reduced high-density lipoprotein (HDL), and increased low-density lipoprotein (LDL)
particles].
 Polycystic ovary syndrome (PCOS) is a common disorder that affects premenopausal
women and is characterized by chronic anovulation and hyperandrogenism.
 Insulin resistance is seen in a significant subset of women with PCOS, and the disorder
substantially increases the risk for type 2 DM, independent of the effects of obesity.
 Insulin Resistance Syndromes
 The metabolic syndrome, the insulin resistance syndrome, or syndrome X are terms used
to describe a constellation of metabolic derangements that includes insulin resistance,
hypertension, dyslipidemia (decreased HDL and elevated triglycerides), central or visceral
obesity, type 2 diabetes or IGT/IFG, and accelerated cardiovascular disease.
 The Metabolic Syndrome
IDF Criteria
• Central obesity (Waist circumference  94 cm for men
and  80 cm for women)
• Plus any two of the following four factors
– TG 150 mg/dl, or specific treatment for this lipid abnormality

– HDL <40 mg/dl in males and <50 mg/dl in females, or specific

treatment for this lipid abnormality
– Systolic BP 130 or diastolic BP 85 mmHg, or treatment of
previously diagnosed hypertension
– Fasting plasma glucose 100 mg/dl, or previously diagnosed type
2 diabetes.
Approach to DM patient
History

 A family history of DM and its complications, risk factors for cardiovascular disease,
exercise, smoking, and ethanol use.
 Symptoms of hyperglycemia include polyuria (osmotic diuresis), polydipsia(increased
osmolality), weight loss, fatigue, weakness, blurry vision, frequent superficial infections
(vaginitis, fungal skin infections), and slow healing of skin lesions after minor trauma.
 Blurred vision results from changes in the water content of the lens.
 In a patient with established DM, the initial assessment should also include special
emphasis on prior diabetes care, including the type of therapy, prior A1C levels, self-
monitoring blood glucose results, frequency of hypoglycemia, presence of DM-specific
complications, and assessment of the patient's knowledge about diabetes, exercise, and
nutrition.
 In addition, the presence of DM-related comorbidities (cardiovascular disease,
hypertension, dyslipidemia).
Physical Examination

 weight or BMI, retinal examination, blood pressure, foot examination, peripheral pulses,
and insulin injection sites.
 BP >130/80 mmHg is considered hypertension in individuals with diabetes.
 Careful examination of the lower extremities should seek evidence of peripheral arterial
disease (pedal pulses), peripheral neuropathy, calluses, superficial fungal infections, nail
disease, ankle reflexes, and foot deformities (such as hammertoes or claw toes and
Charcot foot) in order to identify sites of potential skin ulceration.
 Vibratory sensation (at the base of the great toe), the ability to sense touch , pinprick
sensation, testing for ankle reflexes, and vibration perception threshold are used to
detect moderately advanced diabetic neuropathy.
 Since periodontal disease is more frequent in DM, the teeth and gums should also be
examined.
 Prevention
 Type 2 DM is preceded by a period of IGT or IFG, and a number of lifestyle modifications
and pharmacologic agents prevent or delay the onset of DM.
 changes in lifestyle (diet and exercise for 30 min/d five times/week).
 maintain a normal BMI and engage in regular physical activity.
 metformin
Management of Type 1 DM
Management Components

 Education
 Establish Targets
 Diet
 Exercise
 Reduction of Risk Factors
 Medications
– Oral agents - Type 2
– Insulin – Type 1 & Type 2
Treatment Targets

 A1C: <7%
 Preprandial capillary plasma glucose:70–130 mg/dL
 Peak postprandial capillary plasma glucose: <180 mg/dL
 Blood pressure:<130/80
 LDL: <100mg/dl
 HDL:>40mg/dl (for male), >50mg/dl (for women)
 Triglycerides: <150mg/dl
 ABC of Diabetes Management
Hyperglycemia FBS 90-130 mg/dl

PPG < 180, <160, <140

HbA1C < 7%

Blood Pressure < 130/80 mmHg No Nephropathy

< 125/75 With Nephropathy
Cholesterol Total Cholesterol < 200 mg/dl
LDL-C < 100 mg/dl (only DM)
< 70 mg/dl (DM+CVD)

HDL-C >40 mg/dl (men)

> 50 mg/dl (women)

Triglyceride < 150 mg/dl

Education
 Cornerstone of Therapy
 Lifelong
 Components
– Causes of diabetes
– Symptoms and signs of diabetes
– Components of its management: Insulin injections, etc
– Selfcare (with adequate emphasis on oral hygiene and
foot care, SMBG )
– Acute complications: hypoglycemia, ketoacidosis,
infections
– Chronic complications
Diet
 No one diabetic diet for all
 Avoid Simple Sugars(sugar, soft drinks, honey, and other sweets)
 High CHO
 Low Fat
 High fiber diet such as vegetables slow the absorption of digested food in the form of
simple sugars
 Fruits and Vegetables
 Patients are advised to significantly decrease cholesterol intake.
 Maintenance of a normal Body Mass Index
 Alcohol ingestion should be limited
 Diet should include 60% to 65% carbohydrates, 25% to 35% fat, and 10% to 20% protein.
Physical activity
 Exercise is an integral component of the diabetic
treatment regimen. It has the following
advantages:
– improves peripheral action of insulin
– facilitates glucose uptake and thus lowers blood glucose
– helps attain an ideal body weight
– reduces blood pressure
– Cardiovascular risk reduction
– improves lipid profile
– increases general well being and quality of life
 Aerobic(walking,jogging,swimming), Stretch,
Strength Exercises
 > 4 times per week for 30-60 min each day
Pharmacologic

 Insulin
 Continuous SC insulin infusion (CSII) is a very effective insulin regimen for the patient
with type 1 diabetes.
 In general, individuals with type 1 DM require 0.5–1 U/kg per day of insulin divided into
multiple doses, with 50% of the insulin given as basal insulin.
 Shortcoming of current insulin regimens is that injected insulin immediately enters the
systemic circulation, whereas endogenous insulin is secreted into the portal venous
system. Thus, exogenous insulin administration exposes the liver to sub physiologic
insulin levels.
Methods of Insulin Administration
• Insulin 0.2-0.4 U/kg/day
• Adjust dose by ~ 4 U Every 3-5 days
• Initial Regimen should be Simple

• Standard (Conventional)
– Prolonged duration insulin
– With or Without Short-acting Insulin
– Once daily dose – no more acceptable
– BID dosing even at a small dose
Type 2 DM Treatment
Type 2 DM Treatment

 The goals of therapy for type 2 DM are similar to those in type 1.

 While glycemic control tends to dominate the management of type 1 DM, the care of
individuals with type 2 DM must also include attention to the treatment of conditions
associated with type 2 DM (obesity, hypertension, dyslipidemia, cardiovascular disease)
and detection/management of DM-related complications .
 DM-specific complications may be present in up to 20–50% of individuals with newly
diagnosed type 2 DM.
Management Components

 Education
 Establish Targets
 Diet
 Exercise
 Reduction of Risk Factors
 Medications
– Oral agents - Type 2
– Insulin – Type 1 & Type 2
Education
 Cornerstone of Therapy
 Lifelong
 Components
– Causes of diabetes
– Symptoms and signs of diabetes
– Components of its management: Insulin injections, etc
– Selfcare (with adequate emphasis on oral hygiene and
foot care, SMBG )
– Acute complications: hypoglycemia, ketoacidosis,
infections
– Chronic complications
Treatment Targets

 A1C: <7%
 Preprandial capillary plasma glucose:70–130 mg/dL
 Peak postprandial capillary plasma glucose: <180 mg/dL
 Blood pressure:<130/80
 LDL: <100mg/dl
 HDL:>40mg/dl (for male), >50mg/dl (for women)
 Triglycerides: <150mg/dl
 ABC of Diabetes Management
Hyperglycemia FBS 90-130 mg/dl

PPG < 180, <160, <140

HbA1C < 7%
Blood Pressure < 130/80 mmHg No Nephropathy
< 125/75 With Nephropathy
Cholesterol Total Cholesterol < 200 mg/dl
LDL-C < 100 mg/dl (only DM)
< 70 mg/dl (DM+CVD)
HDL-C >40 mg/dl (men)
> 50 mg/dl (women)
Triglyceride < 150 mg/dl
Diet
 No one diabetic diet for all
 Avoid Simple Sugars(sugar, soft drinks, honey, and other sweets)
 High CHO
 Low Fat
 High fiber diet such as vegetables slow the absorption of digested food in the form of
simple sugars
 Fruits and Vegetables
 Patients are advised to significantly decrease cholesterol intake.
 Maintenance of a normal Body Mass Index
 Alcohol ingestion should be limited
 Diet should include 60% to 65% carbohydrates, 25% to 35% fat, and 10% to 20% protein.
Physical activity
 Exercise is an integral component of the diabetic
treatment regimen. It has the following advantages:
– improves peripheral action of insulin
– facilitates glucose uptake and thus lowers blood glucose
– helps attain an ideal body weight
– reduces blood pressure
– Cardiovascular risk reduction
– improves lipid profile
– increases general well being and quality of life
 Aerobic(walking,jogging,swimming), Stretch, Strength
Exercises
 > 4 times per week for 30-60 min each day
Global Management of Type 2 DM

Glycemic control
Screen/Manage Cx
• Diet
• Exercise • Retinopathy
• Medications • CVD
• Nephropathy
Rx of Associated • Neuropathy
Factors • Others

• Dyslipidemia
• HPN
• Obesity
• Hypercoagulability
• CHD
Pharmacologic

 Pharmacologic approaches to the management of type 2 DM include oral glucose-

lowering agents, insulin.
 Oral glucose-lowering agents are the initial choice.
 Glucose-Lowering Agents
 other than insulin (with the exception of amylin analogue and -glucosidase inhibitors) are
ineffective in type 1 DM and should not be used for glucose management of severely ill
individuals with type 2 DM.
 Insulin is sometimes the initial glucose-lowering agent in type 2 diabetes
A) Biguanides

 Metformin, representative of this class of agents, reduces hepatic glucose production and
improves peripheral glucose utilization slightly.
 The initial starting dose of 500 mg once or twice a day can be increased to 1000 mg bid.
Because of its relatively slow onset of action and gastrointestinal symptoms with higher
doses, the dose should be escalated every 2–3 wks. Metformin is effective as
monotherapy and can be used in combination with other oral agents or with insulin. The
major toxicity of metformin, lactic acidosis is very rare and can be prevented by careful
patient selection.
 Vitamin B12 levels are 30% lower during metformin treatment. Metformin should not be
used in patients with renal insufficiency [GFR < 60 mL/min], any form of acidosis, CHF,
liver disease, or severe hypoxemia. Metformin should be discontinued in patients who
are seriously ill, in patients who can take nothing orally, and in those receiving
radiographic contrast material. Insulin should be used until metformin can be restarted.
B) Insulin Secretagogues

[Link]
 Stimulate insulin secretion by interacting with the ATP-sensitive potassium channel on
the beta cell. These drugs are most effective in individuals with type 2 DM of relatively
recent onset (<5 years), who have residual endogenous insulin production.
 First-generation sulfonylureas have a longer half-life, a greater incidence of
hypoglycemia, more frequent drug interactions, and are now rarely used.
 Second-generation sulfonylureas have a more rapid onset of action and better coverage
of the postprandial glucose rise, but the shorter half-life of some agents may require
more than once-a-day dosing.
 Sulfonylureas reduce both fasting and postprandial glucose and should be initiated at
low doses and increased at 1- to 2-week intervals based on SMBG. In general,
sulfonylureas increase insulin acutely and thus should be taken shortly before a meal.
 Glimepiride (1-8mg/day)and glipizide (5-40mg/dl)can be given in a single daily dose and
are preferred over glyburide.
 The longer acting ones, have the potential to cause profound and persistent
hypoglycemia.
 Most sulfonylureas are metabolized in the liver to compounds (some of which are active)
that are cleared by the kidney. Thus, their use in individuals with significant hepatic or
renal dysfunction is not advisable.
 Weight gain, a common side effect of sulfonylurea therapy.
2. Incretins
 Amplify glucose-stimulated insulin secretion.
 Agents in this class do not cause hypoglycemia because of the glucose-dependent nature
of incretin-stimulated insulin secretion.
 exenatide has prolonged GLP-1-like action and binds to GLP-1 receptors found in islets,
the gastrointestinal tract, and the brain
 Treatment with these agents should start at a low dose to minimize initial side effects
(nausea being the limiting one).
 Exenatide is approved for monotherapy and for use as combination therapy with
metformin, sulfonylureas, and thiazolidinediones.
 GLP-1 receptor agonists should not be used in patients taking insulin. The major side
effects are nausea, vomiting, and diarrhea; pancreatitis and reduced renal function have
been reported in surveillance data with exenatide.
C) Alpha-Glucosidase Inhibitors

 Alpha-Glucosidase inhibitors (acarbose and miglitol) reduce postprandial hyperglycemia

by delaying glucose absorption; they do not affect glucose utilization or insulin secretion.
 These drugs, taken just before each meal, reduce glucose absorption by inhibiting the
enzyme that cleaves oligosaccharides into simple sugars in the intestinal lumen. Therapy
should be initiated at a low dose (25 mg of acarbose or miglitol) with the evening meal
and may be increased to a maximal dose over weeks to months (50–100 mg for acarbose
or 50 mg for miglitol with each meal).
 The major side effects (diarrhea, flatulence, abdominal distention) are related to
increased delivery of oligosaccharides to the large bowel and can be reduced somewhat
by gradual upward dose titration.
 These agents should not be used in individuals with inflammatory bowel disease,
gastroparesis, or a serum creatinine >177 mol/L (2 mg/dL). This class of agents is not as
potent as other oral agents in lowering the A1C but is unique because it reduces the
postprandial glucose rise even in individuals with type 1 DM.
D) Insulin Therapy in Type 2 DM

 Insulin should be considered as the initial therapy in type 2 DM, particularly in lean
individuals or those with severe weight loss, in individuals with underlying renal or
hepatic disease that precludes oral glucose-lowering agents, or in individuals who are
hospitalized or acutely ill.
 Because endogenous insulin secretion continues and is capable of providing some
coverage of mealtime caloric intake, insulin is usually initiated in a single dose of long-
acting insulin (0.3–0.4 U/kg per day), given either before breakfast and in the evening
(NPH) or just before bedtime (NPH, glargine, detemir).
Choice of Initial Glucose-Lowering Agent

 Assuming maximal benefit of diet and increased physical activity has been realized,
patients with mild to moderate hyperglycemia [FPG <200–250 mg/dL] often respond well
to a single, oral glucose-lowering agent.
 Patients with more severe hyperglycemia [FPG >250 mg/dL] may respond partially with
oral monotherapy.
 A stepwise approach that starts with a single agent and adds a second agent to achieve
the glycemic target can be used.
 Insulin can be used as initial therapy in individuals with severe hyperglycemia [FPG >250–
300 mg/dL] or in those who are symptomatic from the hyperglycemia.
 Considerable clinical experience exists with metformin and sulfonylureas because they
have been available for several decades.
 A reasonable treatment algorithm for initial therapy uses metformin as initial therapy
because of its efficacy, known side-effect profile, and relatively low cost.
 Metformin has the advantage that it promotes mild weight loss, lowers insulin levels, and
improves the lipid profile slightly.
 Based on SMBG results and the A1C, the dose of metformin should be increased until the
glycemic target is achieved or maximum dose is reached
Combination Therapy with Glucose-Lowering Agents

 A number of combinations of therapeutic agents are successful in type 2 DM, and the
dosing of agents in combination is the same as when the agents are used alone.
 Because mechanisms of action of the first and second agents used are different, the
effect on glycemic control is usually additive.
 If adequate control is not achieved with the combination of two agents (based on
reassessment of the A1C every 3 months), a third oral agent or basal insulin should be
added.
 Treatment with insulin becomes necessary as type 2 DM enters the phase of relative
insulin deficiency (as seen in long-standing DM) and is signaled by inadequate glycemic
control with one or two oral glucose-lowering agents. Insulin alone or in combination
should be used in patients who fail to reach the glycemic target.
 The daily insulin dose required can become quite large (1–2 units/kg per day) as
endogenous insulin production falls and insulin resistance persists.
 Individuals who require >1 unit/kg per day of long-acting insulin should be considered for
combination therapy with metformin or a thiazolidinedione.
 Insulin plus a thiazolidinedione promotes weight gain and is associated with peripheral
edema.
Complications of Therapy for Diabetes Mellitus

 Side effects of intensive treatment include hypoglycemia, weight gain, increased

economic costs, and greater demands on the patient.
 The most serious complication of therapy for DM is hypoglycemia, and its treatment with
oral glucose or glucagon injection.
 The weight gain is partially due to the anabolic effects of insulin and the reduction in
glucosuria.
Acute Complications of DM
Acute Complications of DM

 Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are acute
complications of diabetes. DKA was formerly considered a hallmark of type 1 DM, but
also occurs in individuals who lack immunologic features of type 1 DM.
 HHS is primarily seen in individuals with type 2 DM.
Diabetic ketoacidosis

 Glucose : 250–600 mg/dL

 Sodium: 125–135 meq/L
 Potassium :Normal to increase
 Serum bicarbonate: <15 meq/L
 Osmolality : 300–320 mOsm/mL
 Plasma ketones: +++++
 Arterial: pH 6.8–7.3
 Anion gap [Na – (Cl + HCO3)]: increase
Hyperglycemic hyperosmolar state

 Glucose : 600-1200 mg/dL

 Sodium: 135-145 meq/L
 Potassium :Normal
 Serum bicarbonate: Normal to decrease
 Osmolality : 330–380 mOsm/mL
 Plasma ketones: +/-
 Arterial: pH >7.3
Diabetic ketoacidosis

DKA
HHS
Hypoglycemia
Diabetic ketoacidosis

 Pathophysiology
 DKA results from relative or absolute insulin deficiency combined with counter regulatory
hormone excess (glucagon, catecholamines, cortisol, and growth hormone).
 The decreased ratio of insulin to glucagon promotes gluconeogenesis, glycogenolysis, and
ketone body formation in the liver, as well as increases in substrate delivery from fat and
muscle (free fatty acids, amino acids) to the liver.
 DKA was formerly considered as a hall mark of type 1 DM. However, currently it is known
that some type 2 DM patients who are being treated by oral hypoglycemic agent may
also develop DKA.
 Impairs glucose uptake into skeletal muscle and fat and reduces intracellular glucose
metabolism.
 Ketosis results from a marked increase in free fatty acid release from adipocytes, with a
resulting shift toward ketone body synthesis in the liver.
 Reduced insulin levels, in combination with elevations in catecholamines and growth
hormone, increase lipolysis and the release of free fatty acids.
 Normally, these free fatty acids are converted to triglycerides or VLDL in the liver.
However, in DKA, hyperglucagonemia alters hepatic metabolism to favor ketone body
formation.
 At physiologic pH, ketone bodies exist as ketoacids, which are neutralized by bicarbonate.
As bicarbonate stores are depleted, metabolic acidosis ensues. Increased lactic acid
production also contributes to the acidosis.
 The increased free fatty acids increase triglyceride and VLDL production.
 Hypertriglyceridemia may be cause pancreatitis.
 Clinical Features
 Hyperglycemia leads to glucosuria, volume depletion, and tachycardia. Hypotension can
occur because of volume depletion in combination with peripheral vasodilatation.
Signs and symptoms

 Volume depletion : dehydration- dry tongue and bucal mucosa , poor skin turgor and
hypotension
 Kussmaul respiration : deep and fast breathing resulting from metabolic acidosis
 Nausea ,vomiting , Thirst/polyuria ,Abdominal pain ,Shortness of breath
 Mental status changes : lethargy and confusion which may evolve into coma with sever
 fruity odour of breath: due too acetone
 Cerebral edema: an extremely serious complication of DKA is seen most frequently in
children.
 Signs of infection , which may be precipitating DKA , should be looked for
 A history of diabetes (unless first presentation).
 KA 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.
 The earliest symptoms of marked hyperglycemia are polyuria, polydipsia, and weight loss.
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.
Precipitating events
 Inadequate insulin administration
 Infection (pneumonia, UTI, gastroenteritis, sepsis)
 Infarction (cerebral, coronary, mesenteric, peripheral)
 Drugs (cocaine)
 Pregnancy
Laboratory Abnormalities and Diagnosis

 DKA is characterized by hyperglycemia, ketosis, and metabolic acidosis (increased anion

gap).
 Despite a total-body potassium deficit, the serum potassium at presentation may be
mildly elevated, secondary to the acidosis. Total-body stores of sodium, chloride,
phosphorus, and magnesium are reduced in DKA but are not accurately reflected by their
levels in the serum because of dehydration and hyperglycemia.
 Elevated blood urea nitrogen (BUN) and serum creatinine levels reflect intravascular
volume depletion.
 Interference from acetoacetate may falsely elevate the serum creatinine measurement.
Leukocytosis, hypertriglyceridemia, and hyperlipoproteinemia are commonly found as
well. Hyperamylasemia may suggest a diagnosis of pancreatitis, especially when
accompanied by abdominal pain. However, in DKA the amylase is usually of salivary origin
and thus is not diagnostic of pancreatitis. Serum lipase should be obtained if pancreatitis
is suspected.
 The measured serum sodium is reduced as a consequence of the hyperglycemia 1.6 meq
reduction in serum sodium for each 100 mg/dL rise in the serum glucose.
 In "conventional" units, the calculated serum osmolality [2 x (serum sodium + serum
potassium) + plasma glucose (mg/dL)/18 + BUN/2.8]
 In DKA, the ketone body, beta-hydroxybutyrate, is synthesized at a threefold greater rate
than acetoacetate; however, acetoacetate is preferentially detected by a commonly used
ketosis detection reagent (nitroprusside).
 Urine dipstick for ketones: ketosis can be determined with bedside reagents. This test is
97% sensitive. Serum keton level can also be measured to confirm hypereketonemia.
 The differential diagnosis of DKA includes starvation ketosis, alcoholic ketoacidosis
(bicarbonate usually >15 meq/L) and other forms of increased anion-gap acidosis.
 CXR, urine culture and sensitivity, blood cultures should also be done to identify an
infectious process
Uptodate

 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:
 ABC status
 Mental status
 Possible precipitating events (eg, source of infection, myocardial infarction)
 Volume status
 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. In addition,
some patients with HHS have focal neurologic signs (hemiparesis or hemianopsia) and/or
seizures [. Mental obtundation may occur in patients with DKA, who have lesser degrees
of hyperosmolality, when severe acidosis is also present
 Effective Posm = [2 x Na (meq/L)] + [glucose (mg/dL) ÷ 18]
 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 are conversion factor from units of mg/dL into mmol/L.
 Effective Posm = [2 x Na (mmol/L)] + glucose (mmol/L)
 Importance of osmotic diuresis — The rise in plasma osmolality in DKA and HHS is only
in part due to the rise in serum glucose. The increase in plasma osmolality pulls water out
of the cells, which reduces the plasma osmolality toward normal and lowers the serum
sodium. The marked hyperosmolality seen in HHS is primarily due to the glucose osmotic
diuresis that causes water loss in excess of sodium and potassium.
 Abdominal pain in DKA — Patients with DKA may present with nausea, vomiting, and
abdominal pain; although more common in children, these symptoms can be seen in
adults.
 Possible causes of abdominal pain include delayed gastric emptying and ileus induced by
the metabolic acidosis and associated electrolyte abnormalities. Other causes for
abdominal pain should be sought when it occurs in the absence of severe metabolic
acidosis and when it persists after the resolution of ketoacidosis.
 Fever is rare even in the presence of infection, because of peripheral vasoconstriction
due to hypovolemia.
 In HHS, there is little or no ketoacid accumulation, the serum glucose concentration
frequently exceeds 1000 mg/dL, the plasma osmolality may reach 380 mosmol/kg, and
neurologic abnormalities are frequently present. Most patients with HHS have an
admission pH >7.30, a serum bicarbonate >20 meq/L, a serum glucose >600 mg/dL, and
test negative for ketones in serum and urine.
 DKA is characterized by the triad of hyperglycemia, anion gap metabolic acidosis, and
ketonemia.
LABORATORY FINDINGS

 Hyperglycemia and hyperosmolality are the two primary laboratory findings in patients
with DKA or HHS; patients with DKA also have a high anion gap metabolic acidosis. Most
patients also have acute elevations in the blood urea nitrogen (BUN) and serum
creatinine concentration, which reflect the reduction in glomerular filtration rate induced
by hypovolemia.
 Serum glucose
 At least two factors contribute to the lesser degree of hyperglycemia in DKA compared
with HHS:
 Patients with DKA often present early with symptoms of ketoacidosis (such as shortness
of breath and abdominal pain), rather than late with those of hyperosmolality.
 Patients with DKA tend to be young and to have a good glomerular filtration rate that. As
a result, they have a much greater capacity to excrete glucose than the usually older
patients with HHS, thereby limiting the degree of hyperglycemia.
 Serum ketones — Three ketone bodies are produced in DKA: acetoacetic acid, which is
the only true ketoacid; beta-hydroxybutyric acid, and acetone, which is derived from the
decarboxylation of acetic acid . Acetone is a true ketone but is chemically neutral and
therefore not an acid.
 Urine ketone bodies are detected by a dipstick. Testing for serum ketones is performed if
urine testing is positive, using nitroprusside (Acetest) tablets or reagent sticks. A 4+
reaction with serum diluted 1:1 is strongly suggestive of ketoacidosis.
 False negative tests — Nitroprusside reacts with acetoacetate and acetone, but not with
beta-hydroxybutyrate . This is important because beta-hydroxybutyrate is the
predominant ketone, particularly in severe DKA. It is therefore possible, although
unusual, to have a negative serum nitroprusside reaction in the presence of severe
ketosis [ 11,36 ].
 An indirect method to circumvent the masking of ketoacidosis is to add a few drops of
hydrogen peroxide to a urine specimen. This will nonenzymatically convert beta-
hydroxybutyrate to acetoacetate, which will then be detectable by nitroprusside [ 38 ].
An alternative is to directly measure beta-hydroxybutyrate in the blood; monitors are
available to measure beta-hydroxybutyrate at the bedside, but this assay may not be
available in many hospitals [ 39,40 ].
 False positive tests — Sulfhydryl drugs, such as captopril , penicillamine , and mesna ,
interact with the nitroprusside reagent and can lead to a false positive ketone test [ 41 ].
Thus, a positive nitroprusside test cannot be reliably interpreted in patients treated with
these drugs and direct measurement of beta-hydroxybutyrate is recommended. If it is
not available, the diagnosis of DKA in this setting should be made on the basis of clinical
presentation and an otherwise unexplained high anion gap metabolic acidosis in
association with hyperglycemia.
Management of DKA

 After initiating IV fluid replacement and insulin therapy, the agent or event that
precipitated the episode of DKA should be sought and aggressively treated.
 If the patient is vomiting or has altered mental status, a nasogastric tube should be
inserted to prevent aspiration of gastric contents.
 When hemodynamic stability and adequate urine output are achieved, IV fluids should be
switched to 0.45% saline depending on the calculated volume deficit.
 The change to 0.45% saline helps to reduce the trend toward hyperchloremia later in the
course of DKA.
 Alternatively, initial use of lactated Ringer's IV solution may reduce the hyperchloremia
that commonly occurs with normal saline.
 IV administration is preferred (0.1 units/kg of regular insulin per hour), because it ensures
rapid distribution and allows adjustment of the infusion rate as the patient responds to
therapy. In mild episodes of DKA, short-acting insulin analogues can be used SC. IV insulin
should be continued until the acidosis resolves and the patient is metabolically stable.
 As the acidosis and insulin resistance resolve, the insulin infusion rate can be decreased
(to 0.05–0.1 units/kg per hour). Long-acting insulin, in combination with SC short-acting
insulin, should be administered as soon as the patient resumes eating.
 It is crucial to continue the insulin infusion until adequate insulin levels are achieved by
administering long-acting insulin by the SC route.
 Hyperglycemia usually improves at a rate of 75–100 mg/dL per hour as a result of insulin-
mediated glucose disposal, reduced hepatic glucose release, and rehydration..
 When the plasma glucose reaches 200 mg/dL, glucose should be added to the 0.45%
saline infusion to maintain the plasma glucose in the 150–250 mg/dL range, and the
insulin infusion should be continued.
 Ketoacidosis begins to resolve as insulin reduces lipolysis, increases peripheral ketone
body use, suppresses hepatic ketone body formation, and promotes bicarbonate
regeneration.
 However, the acidosis and ketosis resolve more slowly than hyperglycemia. As
ketoacidosis improves, beta-hydroxybutyrate is converted to acetoacetate. Ketone body
levels may appear to increase if measured by laboratory assays that use the nitroprusside
reaction, which only detects acetoacetate and acetone.
 The improvement in acidosis and anion gap, a result of bicarbonate regeneration and
decline in ketone bodies, is reflected by a rise in the serum bicarbonate level and the
arterial pH. Depending on the rise of serum chloride, the anion gap (but not bicarbonate)
will normalize.
 A hyperchloremic acidosis [serum bicarbonate of 15–18 mmol/L (meq/L)] often follows
successful treatment and gradually resolves as the kidneys regenerate bicarbonate and
excrete chloride.
 Various factors contribute to the development of hypokalemia. These include insulin-
mediated potassium transport into cells, resolution of the acidosis (which also promotes
potassium entry into cells), and urinary loss of potassium salts of organic acids.
 Thus, potassium repletion should commence as soon as adequate urine output and a
normal serum potassium are documented. If the initial serum potassium level is elevated,
then potassium repletion should be delayed until the potassium falls into the normal
range. Inclusion of 20–40 meq of potassium in each liter of IV fluid is reasonable, but
additional potassium supplements may also be required.
 To reduce the amount of chloride administered, potassium phosphate or acetate can be
substituted for the chloride salt. The goal is to maintain the serum potassium at >3.5
mmol/L (3.5 meq/L).
 Despite a bicarbonate deficit, bicarbonate replacement is not usually necessary.
 However, in the presence of severe acidosis (arterial pH <6.9), the ADA advises
bicarbonate [50 mmol/L (meq/L) of sodium bicarbonate in 200 mL of sterile water with
10 meq/L KCl per hour for 2 h until the pH is >7.0].
 Hypophosphatemia may result from increased glucose usage, but phosphate
replacement is not beneficial in DKA.
 If the serum phosphate <1 mg/dL, then phosphate supplement should be considered and
the serum calcium monitored.
 Hypomagnesemia may develop during DKA therapy and may also require
supplementation.
 With appropriate therapy, the mortality rate of DKA is low (<1%) and is related more to
the underlying or precipitating event, such as infection or myocardial infarction. Venous
thrombosis, upper gastrointestinal bleeding, and acute respiratory distress syndrome
occasionally complicate DKA.
Management of DKA

1) Confirm diagnosis;
 plasma glucose,
 positive serum ketones,
 metabolic acidosis
2) Admit to hospital; intensive-care setting may be necessary for frequent
monitoring or if pH<7.00 or unconscious.
3) Assess:
 Serum electrolytes
 Acid-base status—pH, HCO3–, PCO2,beta hydroxybutyrate
 Renal function (creatinine, urine output)
4) Replace fluids: 2–3 L of 0.9% saline over first 1–3 h ? (15–20 mL/kg per hour);
subsequently, 0.45% saline at 250–500 mL/h; change to 5% glucose and
0.45% saline at 150–250 mL/h when plasma glucose reaches 200 mg/dL.
5) Administer short-acting insulin: IV (0.1 units/kg), then 0.1 units/kg per hour
by continuous IV infusion; increase two- to threefold if no response by 2–4 h.
If the initial serum potassium is <3.3 mmol/L (3.3 meq/L), do not administer
insulin until the potassium is corrected. If the initial serum potassium is >5.2
mmol/L (5.2 meq/L), do not supplement K+ until the potassium is corrected.
6) Assess patient: What precipitated the episode (noncompliance, infection,
trauma, infarction, cocaine)? Initiate appropriate workup for precipitating
event (cultures, CXR, ECG).
7) Measure capillary glucose every 1–2 h; measure electrolytes (especially K+,
bicarbonate, phosphate) and anion gap every 4 h for first 24 h.
8) Monitor blood pressure, pulse, respirations, mental status, fluid intake and
output every 1–4 h
9) Replace K+: 10 meq/h when plasma K+ < 5.0–5.2 meq/L, ECG normal, urine
flow and normal creatinine documented; administer 40–80 meq/h when
plasma K+ < 3.5 meq/L or if bicarbonate is given.
10)Continue above until patient is stable, glucose goal is 150–250 mg/dL, and
acidosis is resolved. Insulin infusion may be decreased to 0.05–0.1 units/kg
per hour.
11)Administer long-acting insulin as soon as patient is eating. Allow for overlap
in insulin infusion and SC insulin injection.
Prevention of DKA

 Foremost is patient education about the symptoms of DKA, its precipitating factors, and
the management of diabetes during a concurrent illness. (1) frequently measure the
capillary blood glucose; (2) measure urinary ketones when the serum glucose > 300
mg/dL); (3) drink fluids to maintain hydration; (4) continue or increase insulin; and (5)
seek medical attention if dehydration, persistent vomiting, or uncontrolled
hyperglycemia develop.
Hyperglycemic Hyperosmolar State
Hyperglycemic Hyperosmolar State

 Usually occurs in elderly type 2 DM patients that do not develop ketosis

 It is often precipitated by serious intercurrent illnesses such as myocardial infarction,
stroke, pneumonia, sepsis
 Pathophysiology
 Relative insulin deficiency and inadequate fluid intake are the underlying causes of HHS.
Insulin deficiency increases hepatic glucose production (through glycogenolysis and
gluconeogenesis) and impairs glucose utilization in skeletal muscle.
 Hyperglycemia induces an osmotic diuresis that leads to intravascular volume depletion,
which is exacerbated by inadequate fluid replacement. The absence of ketosis in HHS is
not understood.
 Insulin deficiency is only relative and less severe than in DKA. Lower levels of
counterregulatory hormones and free fatty acids have been found in HHS than in DKA .
 The insulin/glucagon ratio does not favor ketogenesis.
Clinical Features

 Several-week history of polyuria, weight loss, and diminished oral intake that culminates
in mental confusion, lethargy, or coma.
 Profound dehydration and hyperosmolality and reveals hypotension, tachycardia, and
altered mental status.
 Absent symptoms of nausea, vomiting, and abdominal pain and the Kussmaul
respirations characteristic of DKA
 HHS is often precipitated by a serious, concurrent illness such as myocardial infarction or
stroke, Sepsis, pneumonia, and other serious infections are frequent precipitants and
should be sought.
 In addition, a debilitating condition (prior stroke or dementia) or social situation that
compromises water intake usually contributes to the development of the disorder.
Laboratory Abnormalities

 In contrast to DKA, acidosis (secondary to increased lactic acid ) and ketonemia

(secondary to starvation) are absent or mild.
 Glucose : 600-1200 mg/dL
 Sodium: 135-145 meq/L
 Potassium :Normal
 Serum bicarbonate: Normal to decrease
 Osmolality : 330–380 mOsm/mL
 Plasma ketones: +/-
 Arterial: pH >7.3
Treatment

 Therapy of HHS and DKA shares several elements in common.

 Underlying or precipitating problems should be aggressively sought and treated.
 In HHS, fluid losses and dehydration are usually more pronounced than in DKA due to the
longer duration of the illness.
 The patient with HHS is usually older, more likely to have mental status changes, and
more likely to have a life-threatening precipitating event with accompanying
comorbidities.
 Even with proper treatment, HHS has a substantially higher mortality rate than DKA (up
to 15% in some clinical series).
 Fluid replacement should initially stabilize the hemodynamic status of the patient (1–3 L
of 0.9% normal saline over the first 2–3 h).
 If the serum sodium > 150 mmol/L (150 meq/L), 0.45% saline should be used.
 Potassium repletion is usually necessary and should be dictated by repeated
measurements of the serum potassium.
 Hypophosphatemia may occur during therapy and can be improved by using KPO4 and
beginning nutrition.
 After hemodynamic stability is achieved, the IV fluid administration is directed at
reversing the free water deficit using hypotonic fluids (0.45% saline initially, then 5%
dextrose in water, D5W). The calculated free water deficit (which averages 9–10 L)
should be reversed over the next 1–2 days (infusion rates of 200–300 mL/h of hypotonic
solution).
 An IV insulin bolus of 0.1 units/kg followed by IV insulin at a constant infusion rate of 0.1
units/kg per hour.
 If the serum glucose does not fall, increase the insulin infusion rate by twofold. As in DKA,
glucose should be added to IV fluid when the plasma glucose falls to 250–300 mg/dL, and
the insulin infusion rate should be decreased to 0.05–0.1 units/kg per hour.
 The insulin infusion should be continued until the patient has resumed eating and can be
transferred to a SC insulin regimen.
 The patient should be discharged from the hospital on insulin, though some patients can
later switch to oral glucose-lowering agents.
Hypoglycemia
Hypoglycemia
 Common Complication in Type 1 DM
 Principal Limiting Factor in Management of DM
 Mortality 2-4%
 Psychosocial Distress ( Fear of Hypo)
 More in Intensively Treated Patients
 < 50 mg/dl
Hypoglycemia (cont’d)

 Must be Rapidly Differentiated from DKA & HHS

 Therapy is Different
 If Unsure of Cause of Coma - 40% Glucose 40cc IV
Causes of Hypoglycemia

 Excessive Insulin or OHA

 Omission or Delay of Meals
 Unusually Excessive Physical Activity
Manifestations of Hypoglycaemia
Related to Sympathetic Hyperactivity (early)
– Palpitations
– Sweating
– Tremulousness
Related to
Neuroglycopaenia(late):hypoglycemia on
the brain
– Confusion
– Blank stare (like petit mal)
– Maniacal or drunken behaviour
– Unconsciousness
– Convulsions
Hypoglycaemia Occurring During Sleep

 Headache
 Tongue bite
 Nightmares
 Torn bed sheets
 Urinary (foecal) incontinence
Management of Hypoglycemia

 Any patient with diabetes losing consciousness should always be considered

hypoglycemic until proven otherwise by blood sugar determination
 Management of Hypoglycemia

 Sugary Drinks
 40% Glucose IV Push 20-40 cc
 5% D/W Infusion + 40% Glucose
 Glucagon 1 mg IM (in Home Setting)
 Observe if Hypo after OHA(oral hypoglycemic agent)
 Educate Patient on Hypoglycemia
Long-term Complications
Chronic Complications of Diabetes

Macrovascular Microvascular

Diabetic
Cerebrovascular Eye
Disease Disease

Diabetic
Cardiovascular Diabetes Kidney
Disease Mellitus Disease

Diabetic
Peripheral
Nerve
Arterial
Disease
Disease
Cont’d

A. Retinopathy
B. Nephropathy
C. Neuropathy
D. Foot Ulcer
 Chronic complications can be divided into vascular and nonvascular complications.
 The vascular complications of DM are further subdivided into microvascular (retinopathy,
neuropathy, nephropathy) and macrovascular complications [coronary heart disease
(CHD), peripheral arterial disease (PAD), cerebrovascular disease].
 Nonvascular complications include gastroparesis, infections, Periodontal disease,
Glaucoma, skin changes, uropathy/sexual dysfunction ,hearing loss.
 The risk of chronic complications increases as a function of the duration and degree of
hyperglycemia.
 Since type 2 DM often has a long asymptomatic period of hyperglycemia, many
individuals with type 2 DM have complications at the time of diagnosis.
 The microvascular complications of both type 1 and type 2 DM result from chronic
hyperglycemia.
Mechanisms of Complications

 Four prominent theories, have been proposed to explain how hyperglycemia might lead
to the chronic complications of DM.
 I don’t want to know them!
Retinopathy
Retinopathy

 Blindness is primarily the result of progressive diabetic retinopathy and macular edema.
 Diabetic retinopathy is classified into two stages: nonproliferative and proliferative.
 Nonproliferative diabetic retinopathy usually appears late in the first decade or early in
the second decade of the disease and is marked by retinal vascular microaneurysms, blot
hemorrhages, and cotton-wool spots.
 The pathophysiologic mechanisms invoked in nonproliferative retinopathy include loss of
retinal pericytes, increased retinal vascular permeability, alterations in retinal blood flow,
and abnormal retinal microvasculature, all of which lead to retinal ischemia.
 The appearance of neovascularization in response to retinal hypoxemia is the hallmark of
proliferative diabetic retinopathy.
 These newly formed vessels appear near the optic nerve and/or macula and rupture
easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment.
 Not all individuals with nonproliferative retinopathy develop proliferative retinopathy,
but the more severe the nonproliferative disease, the greater the chance of evolution to
proliferative retinopathy.
 Duration of DM and degree of glycemic control are the best predictors of the
development of retinopathy; hypertension is also a risk factor.
Treatment

 The most effective therapy for diabetic retinopathy is prevention.

 Glycemic and blood pressure control will slow the progression of retinopathy.
 Individuals with known retinopathy are candidates for prophylactic photocoagulation
when initiating intensive therapy.
 Regular, comprehensive eye examinations are essential for all individuals with DM.
 Laser photocoagulation is very successful in preserving vision.
Nephropathy
Nephropathy

 A leading cause of DM-related morbidity and mortality.

 Both microalbuminuria and macroalbuminuria in individuals with DM are associated with
increased risk of cardiovascular disease.
 Because only 20–40% of patients with diabetes develop diabetic nephropathy, additional
susceptibility factors remain unidentified. One known risk factor is a family history of
diabetic nephropathy.
 Glomerular hyperperfusion and renal hypertrophy occur in the first years after the onset
of DM and with an increase of the GFR.
 During the first 5 years of DM, thickening of the glomerular basement membrane,
glomerular hypertrophy, and mesangial volume expansion occur as the GFR returns to
normal.
 After 5–10 years of type 1 DM, 40% of individuals begin to excrete small amounts of
albumin in the urine.
 Microalbuminuria is defined as 30–299 mg/d in a 24-h collection or 30–299 g/mg
creatinine in a spot collection.
 Microalbuminuria is an important risk factor for progression to macroalbuminuria (>300
mg/d or > 300 g/mg creatinine),over the next 10 years
 Once macroalbuminuria is present, there is a steady decline in GFR, and 50% of
individuals reach ESRD in 7–10 years.
 Once macroalbuminuria develops, blood pressure rises slightly and the pathologic
changes are likely irreversible.
 The nephropathy that develops in type 2 DM differs from that of type 1 DM in the
following respects:
 microalbuminuria or macroalbuminuria may be present when type 2 DM is diagnosed,
reflecting its long asymptomatic period;
 hypertension more commonly accompanies microalbuminuria or macroalbuminuria in
type 2 DM
 microalbuminuria may be less predictive of diabetic nephropathy
Treatment

Interventions effective in slowing progression from microalbuminuria to macroalbuminuria

include
 normalization of glycemia,
 strict blood pressure control
 administration of ACE inhibitors or ARBs.
 Dyslipidemia should abe treated.
 Blood pressure should be maintained at <130/80 mmHg in diabetic individuals.
 If use of either ACE inhibitors or ARBs is not possible or the blood pressure is not
controlled, then calcium channel blockers, beta blockers, or diuretics should be used.
 Renal transplantation from a living related donor is the preferred therapy but requires
chronic immunosuppression.
Neuropathy
 Diabetic neuropathy occurs in 50% of individuals with long-standing type DM.
 It may manifest as polyneuropathy, mononeuropathy, and/or autonomic neuropathy.
 Both myelinated and unmyelinated nerve fibers are lost.
 Polyneuropathy/Mononeuropathy
 The most common form of diabetic neuropathy is distal symmetric polyneuropathy. It
most frequently presents with distal sensory loss.
 Hyperesthesia, paresthesia, and dysesthesia also may occur. Any combination of these
symptoms may develop as neuropathy progresses.
 Symptoms may include a sensation of numbness, tingling, sharpness, or burning that
begins in the feet and spreads proximally. Pain typically involves the lower extremities, is
usually present at rest, and worsens at night.
 As diabetic neuropathy progresses, the pain subsides and eventually disappears, but a
sensory deficit in the lower extremities persists.
 Physical examination reveals sensory loss, loss of ankle reflexes, and abnormal position
sense.
 Diabetic polyradiculopathy is a syndrome characterized by severe disabling pain in the
distribution of one or more nerve roots. It may be accompanied by motor weakness.
 Fortunately, diabetic polyradiculopathies are usually self-limited and resolve over 6–12
months.
 Mononeuropathy (dysfunction of isolated cranial or peripheral nerves) is less common
than polyneuropathy in DM and presents with pain and motor weakness in the
distribution of a single nerve.
 Involvement of the third cranial nerve is most common and is heralded by diplopia.
Physical examination reveals ptosis and ophthalmoplegia with normal pupillary
constriction to light.
 Autonomic Neuropathy
 DM-related autonomic neuropathy can involve multiple systems, including the
cardiovascular, gastrointestinal, genitourinary, sudomotor, and metabolic systems.
 Affection of the cardiovascular system cause a resting tachycardia and orthostatic
hypotension.
 Gastroparesis and bladder-emptying abnormalities are often caused by the autonomic
neuropathy seen in DM.
 Sudden death
 Hyperhidrosis of the upper extremities and anhidrosis of the lower extremities result
from sympathetic nervous system dysfunction.
 Anhidrosis of the feet can promote dry skin with cracking, which increases the risk of foot
ulcers.
 Autonomic neuropathy may reduce counterregulatory hormone release (especially
catecholamines), leading to an inability to sense hypoglycemia
Treatment

 Improved glycemic control should be aggressively pursued

 Hypertension and hypertriglyceridemia should be treated.
 Avoidance of alcohol and smoking, supplementation with vitamins for possible
deficiencies (B12, folate) and symptomatic treatment are the mainstays of therapy.
 Loss of sensation in the foot places the patient at risk for ulceration and its sequelae;
consequently, prevention of such problems is of paramount importance.
 Chronic, painful diabetic neuropathy is difficult to treat but may respond to tricyclic
antidepressants or anticonvulsants.
 Therapy of orthostatic hypotension
Foot Ulcer
 The reasons for the increased incidence of foot ulcer in DM involve the interaction of
several pathogenic factors:
 Neuropathy, abnormal foot biomechanics, PAD, and poor wound healing.
 The peripheral sensory neuropathy interferes with normal protective mechanisms and
allows the patient to sustain trauma to the foot, often without knowledge of the injury.
Disordered proprioception causes abnormal weight bearing while walking and
subsequent formation of callus or ulceration.
 Autonomic neuropathy results in anhidrosis and altered superficial blood flow in the foot,
which promote drying of the skin and fissure formation.
 PAD and poor wound healing impede resolution of minor breaks in the skin, allowing
them to enlarge and to become infected.
 15% of individuals with type 2 DM develop a foot ulcer (great toe or MTP areas are most
common), and a significant subset will ultimately undergo amputation (14–24% risk with
that ulcer or subsequent ulceration).
 Risk factors for foot ulcers or amputation include: male sex, diabetes >10 years' duration,
peripheral neuropathy, abnormal structure of foot (bony abnormalities, callus, thickened
nails), peripheral arterial disease, smoking, history of previous ulcer or amputation, and
poor glycemic control.
 The plantar surface of the foot is the most common site of ulceration. Ulcers may be
primarily neuropathic (no accompanying infection) or may have surrounding cellulitis or
osteomyelitis.
 Cellulitis without ulceration should be treated with antibiotics that provide broad-
spectrum coverage, including anaerobes.
 An infected ulcer is a clinical diagnosis, since superficial culture of any ulceration will
likely find multiple possible bacterial species. The infection surrounding the foot ulcer is
often the result of multiple organisms (gram-positive and -negative organisms and
anaerobes), and gas gangrene may develop in the absence of clostridial infection.
 Cultures taken from the surface of the ulcer are not helpful; a culture from the debrided
ulcer base or from purulent drainage or aspiration of the wound is the most helpful.
 Plain radiographs of the foot assess the possibility of osteomyelitis in chronic ulcers.
 MRI of the foot
Treatment

 The optimal therapy is prevention through identification of high-risk patients, education

of the patient, and care of wound.
 Patient education should emphasize (1) careful selection of footwear, (2) daily inspection
of the feet to detect early signs of poor-fitting footwear or minor trauma
 (3) daily foot hygiene to keep the skin clean and moist, (4) avoidance of self-treatment of
foot abnormalities and high-risk behavior (e.g., walking barefoot), and (5) prompt
consultation with a health care provider if an abnormality arises
 Attention to risk factors for vascular disease (smoking, dyslipidemia, hypertension) and
improved glycemic control are also important.
 Wound care
 (1) off-loading,
 (2) debridement,
 (3) wound dressings,
 (4) appropriate use of antibiotics,
 (5) revascularization, and
 (6) limited amputation
 Off-loading is the complete avoidance of weight bearing on the ulcer and Bed rest
 Dressings such as hydrocolloid dressings
 Antiseptic agents should be avoided. Topical antibiotics are of limited value.
 IV antibiotics should provide broad-spectrum coverage directed toward Staphylococcus
aureus, streptococci, gram-negative aerobes, and anaerobic bacteria
 Severe infections, or infections that do not improve after 48 h of antibiotic therapy,
require expansion of antimicrobial therapy to treat methicillin-resistant S. aureus (e.g.,
vancomycin) and Pseudomonas aeruginosa and reconsideration of the need for surgical
debridement or revascularization.
Infections
Infections

 Hyperglycemia aids the colonization and growth of a variety of organisms (Candida and
other fungal species).
 Several rare infections are seen almost exclusively in the diabetic population. Examples
of this include;
 Rhinocerebral mucormycosis,
 Emphysematous infections of the gall bladder and urinary tract, and
 “Malignant" or invasive otitis externa.

 Invasive otitis externa is usually secondary to P. aeruginosa infection usually begins with
pain and discharge, and may rapidly progress to osteomyelitis and meningitis.
 Pneumonia, urinary tract infections, and skin and soft tissue infections are all more
common in the diabetic population.
 the organisms that cause pulmonary infections are similar to those found in the
nondiabetic population; however, gram-negative organisms, S. aureus, and
Mycobacterium tuberculosis are more frequent pathogens.
 Susceptibility to furunculosis, superficial candidal infections, and vulvovaginitis are
increased.
 Diabetic individuals have an increased rate of colonization of S. aureus in the skinfolds
and nares. Diabetic patients have a greater risk of postoperative wound infections.
Dermatologic Manifestations
 Protracted wound healing and skin ulcerations.
 Diabetic dermopathy, sometimes termed pigmented pretibial papules, or "diabetic skin
spots," begins as an erythematous area and evolves into an area of circular
hyperpigmentation.
 Lipoatrophy and lipohypertrophy can occur at insulin injection sites
 Xerosis and pruritus
Cardiovascular Risk Factors
 Dyslipidemia
 The most common pattern of dyslipidemia is hypertriglyceridemia and reduced HDL
cholesterol levels.
 Hypertension
 Hypertension can accelerate other complications of DM, particularly cardiovascular
disease and nephropathy. In targeting a goal of BP <130/80 mmHg,
Cardiovascular disease
 A marked increase in PAD, CHF, CHD, MI, and sudden death (risk increase from one- to
fivefold) in DM.
 Risk factors for macrovascular disease in diabetic individuals include dyslipidemia,
hypertension, obesity, reduced physical activity, and cigarette smoking.
 Cerebrovascular disease is increased in individuals with DM (threefold increase in stroke).
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