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Clinical Pathology

Role of Laboratory Tests in Diabetes Mellitus

By Dayyal Dg.Twitter Profile | Updated: Monday, 18 December 2023 23:57 UTC
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Female doctor looking at a blood sample.
Female doctor looking at a blood sample. Freepik / @freepik

Diabetes mellitus (DM) is a metabolic group of disorders marked by persistent hyperglycemia, a consequence of insulin deficiency and/or diminished insulin effectiveness. This condition induces disruptions in carbohydrate, protein, and fat metabolism, arising from the failure of insulin action on target cells.

Distinctive features of DM encompass:

  • Fasting hyperglycemia
  • Presence of glycosuria
  • Manifestation of symptoms linked to pronounced hyperglycemia, including polyuria, polydipsia, weight loss, weakness, polyphagia, and blurred vision
  • Long-term complications, such as atherosclerosis leading to ischemic heart disease, cerebrovascular disease, and peripheral vascular disease, and microangiopathy, which can result in nephropathy with a risk of renal failure; retinopathy with potential vision loss; and peripheral neuropathy with a risk of foot ulcers, amputations, or Charcot joints
  • Acute metabolic complications, including hyperosmolar hyperglycemic state and diabetic ketoacidosis
  • Susceptibility to infections, particularly affecting the skin, respiratory tract, and urinary tract.

In DM, applications of laboratory tests are as follows:

  • Diagnosis of DM
  • Screening of DM
  • Assessment of glycemic control
  • Assessment of associated long-term risks
  • Management of acute metabolic complications.

Laboratory Tests for Diagnosis of Diabetes Mellitus

The diagnosis of diabetes mellitus (DM) relies exclusively on the demonstration of elevated blood glucose levels, indicating hyperglycemia. The current diagnostic criteria, as outlined by the American Diabetes Association in 2004, include the following parameters:

  1. Presence of typical symptoms of DM such as polyuria, polydipsia, and weight loss, coupled with a random plasma glucose level of ≥ 200 mg/dl (≥ 11.1 mmol/L).
  2. Fasting plasma glucose level ≥ 126 mg/dl (≥ 7.0 mmol/L).
  3. A 2-hour post glucose load (75 g) value during an oral glucose tolerance test ≥ 200 mg/dl (≥ 11.1 mmol/L).

In the event that any of the above three criteria is met, confirmation through repeat testing on a subsequent day becomes imperative for establishing the diagnosis of DM. However, it's noteworthy that confirmation by repeat testing is waived if the patient presents with either (a) hyperglycemia and ketoacidosis, or (b) hyperosmolar hyperglycemia.

The laboratory tests employed for the diagnosis of DM encompass the estimation of blood glucose levels and the oral glucose tolerance test.

Estimation of Blood Glucose

Assessing carbohydrate metabolism in individuals with diabetes mellitus (DM) can be efficiently accomplished through a straightforward examination of blood glucose levels (refer to Figure 1). Given the body's rapid metabolism of glucose, the measurement of blood glucose serves as a reliable indicator, providing valuable insights into the present status of carbohydrate metabolism.

Blood glucose values in normal individuals
Figure 1: Blood glucose values in normal individuals, prediabetes, and diabetes mellitus

The estimation of glucose concentration can be conducted in various blood specimens, including whole blood (capillary or venous blood), plasma, or serum. It's important to note that the concentration of blood glucose varies depending on the nature of the blood specimen. Specifically, plasma glucose tends to be approximately 15% higher than whole blood glucose, with this discrepancy influenced by the individual's hematocrit levels. During the fasting state, both capillary and venous blood exhibit similar glucose levels. However, in the postprandial or post-glucose load phase, capillary blood values surpass venous blood levels by 20-70 mg/dl. This disparity arises because venous blood is returning after delivering blood to the body's tissues.

When whole blood is allowed to remain at room temperature after collection, glycolysis ensues, leading to a gradual reduction in glucose levels at a rate of approximately 7 mg/dl per hour. The glycolytic process is further heightened in the presence of bacterial contamination or leucocytosis. To mitigate this, the addition of sodium fluoride (2.5 mg/ml of blood) proves effective in maintaining a stable glucose level by inhibiting glycolysis. Sodium fluoride is commonly employed in conjunction with anticoagulants such as potassium oxalate or EDTA.

The incorporation of sodium fluoride becomes unnecessary if plasma is promptly separated from whole blood within 1 hour of the blood collection process. This practice ensures the preservation of glucose levels without the need for additional interventions.

Plasma is the preferred medium for estimating glucose levels, as whole blood glucose can be influenced by the concentration of proteins, particularly hemoglobin.

Various methods exist for assessing blood glucose:

  • Chemical methods:
    1. Orthotoluidine method
    2. Blood glucose reduction methods using neocuproine, ferricyanide, or copper.

While chemical methods are less specific, they offer a cost-effective alternative to enzymatic methods.

  • Enzymatic methods: These methods are specific to glucose.
    1. Glucose oxidase-peroxidase
    2. Hexokinase
    3. Glucose dehydrogenase

Enzymatic methods have superseded chemical methods in contemporary glucose estimation.

Terminology for blood glucose specimens: Different terms are employed based on the time of collection for blood glucose specimens.

  • Fasting blood glucose: A sample for blood glucose is drawn after an overnight fast (no caloric intake for at least 8 hours).
  • Post-meal or postprandial blood glucose: A blood sample for glucose estimation is collected 2 hours after the subject has consumed a regular meal.
  • Random blood glucose: A blood sample is collected at any time of the day, without consideration of the time since the last food intake.

Oral Glucose Tolerance Test (OGTT)

Glucose tolerance pertains to the body's capacity to metabolize glucose. In the context of Diabetes Mellitus (DM), this capability becomes compromised or entirely lost, with glucose intolerance emerging as the foundational pathophysiological anomaly in DM. The Oral Glucose Tolerance Test (OGTT) serves as a provocative examination to evaluate an individual's response to a glucose challenge (refer to Figure 2).

Oral glucose tolerance curve
Figure 2: Oral glucose tolerance curve

The American Diabetes Association discourages the routine use of OGTT for diagnosing type 1 or type 2 diabetes mellitus. This stance stems from the fact that a fasting plasma glucose cutoff value of 126 mg/dl reveals a comparable prevalence of abnormal glucose metabolism in the population as OGTT. Conversely, the World Health Organization (WHO) advocates for OGTT when fasting plasma glucose falls within the impaired fasting glucose range (i.e., 100-125 mg/dl). Both ADA and WHO endorse OGTT as the preferred diagnostic method for gestational diabetes mellitus.

Preparation of the Patient

  • The individual should adhere to a carbohydrate-rich, unrestricted diet for a duration of 3 days. This dietary approach is recommended due to the observed reduction in glucose tolerance associated with a carbohydrate-restricted regimen.
  • The patient should maintain an ambulatory lifestyle with normal physical activity. Prolonged bed rest, even for a few days, has been shown to impair glucose tolerance.
  • All medications should be discontinued on the day of testing to ensure accurate assessment.
  • During the test period, the individual should abstain from exercise, smoking, and the consumption of tea or coffee. It is essential for the patient to remain in a seated position throughout the testing period.
  • The Oral Glucose Tolerance Test (OGTT) should be conducted in the morning, following an overnight fast of 8-14 hours.

Test

  1. In the morning, a fasting venous blood sample is obtained.
  2. The patient is administered 75 g of anhydrous glucose dissolved in 250-300 ml of water over a span of 5 minutes. For pediatric patients, the dose is calculated as 1.75 g of glucose per kg of body weight, up to a maximum of 75 g of glucose. The initiation of the glucose drink marks the 0-hour time point.
  3. A singular venous blood sample is drawn 2 hours after the glucose load. It is noteworthy that the previous practice of collecting blood samples at ½, 1, 1½, and 2 hours is now deemed outdated and not recommended.
  4. Fasting and 2-hour venous blood samples are used to estimate plasma glucose levels.

The interpretation of blood glucose levels can be found in Table 1.

Table 1: Interpretation of oral glucose tolerance test
ParameterNormalImpaired fasting glucoseImpaired glucose toleranceDiabetes mellitus
Fasting (8 hr) < 100 100-125 ≥ 126
2 hr OGTT < 140 < 140 140-199 ≥ 200

Oral Glucose Tolerance Test (OGTT) in Gestational Diabetes Mellitus: The impairment of glucose tolerance is a common occurrence during pregnancy, especially in the second and third trimesters. The American Diabetes Association (ADA) provides the following recent guidelines for the laboratory diagnosis of Gestational Diabetes Mellitus (GDM):

  • Low-risk pregnant women may forego testing if they meet all the following criteria: age below 25 years, normal pre-pregnancy body weight, absence of diabetes in first-degree relatives, belonging to an ethnic group with a low prevalence of diabetes, no history of poor obstetric outcomes, and no prior instances of abnormal glucose tolerance.
  • For average-risk pregnant women, falling between low and high risk, testing is recommended at 24-28 weeks of gestation.
  • High-risk pregnant women—those meeting any one of the following criteria—should undergo immediate testing: marked obesity, a strong family history of diabetes, presence of glycosuria, or a personal history of Gestational Diabetes Mellitus (GDM).

Initially, it is recommended to obtain either fasting plasma glucose or random plasma glucose. If the fasting plasma glucose measures ≥ 126 mg/dl or the random plasma glucose is ≥ 200 mg/dl, a follow-up test should be conducted on a subsequent day to confirm the diagnosis of Diabetes Mellitus (DM). In cases where both initial tests yield normal results, the Oral Glucose Tolerance Test (OGTT) is indicated for both average-risk and high-risk pregnant women.

Two distinct approaches exist for the laboratory diagnosis of Gestational Diabetes Mellitus (GDM):

  • One-Step Approach
  • Two-Step Approach

Within the one-step approach, the patient is administered 100 grams of glucose, and a subsequent 3-hour Oral Glucose Tolerance Test (OGTT) is conducted. This particular testing protocol may prove to be a cost-effective strategy, especially for high-risk pregnant women.

Alternatively, in the two-step approach, an initial screening test is initiated wherein the patient consumes a 50-gram glucose drink, irrespective of the time elapsed since their last meal. A venous blood sample is then collected 1 hour post-ingestion (commonly known as O'Sullivan's test). Gestational Diabetes Mellitus (GDM) is ruled out if the glucose level in the venous plasma sample falls below 140 mg/dl. Conversely, if the glucose level exceeds 140 mg/dl, a comprehensive 100-gram, 3-hour OGTT is subsequently conducted for further evaluation.

During the 3-hour Oral Glucose Tolerance Test (OGTT), blood samples are systematically collected in the morning following an overnight fast lasting 8-10 hours. Subsequent samples are obtained at 1, 2, and 3 hours post-ingestion of 100 grams of glucose. To establish a diagnosis of Gestational Diabetes Mellitus (GDM), glucose concentrations should surpass the designated cut-off values in two or more of the venous plasma samples:

  • Fasting: 95 mg/dl
  • 1 hour: 180 mg/dl
  • 2 hours: 155 mg/dl
  • 3 hours: 140 mg/dl

Laboratory Tests for Screening of Diabetes Mellitus

The primary objective of screening is the identification of asymptomatic individuals with a likelihood of having Diabetes Mellitus (DM). Given that early detection and the prompt initiation of treatment can mitigate subsequent complications associated with DM, screening becomes a judicious course of action in certain scenarios.

Screening for Type 2 DM: Type 2 DM stands as the most prevalent form of DM, typically manifesting as asymptomatic in its initial phases. Its onset transpires approximately 5-7 years prior to clinical diagnosis, with evidence suggesting that complications of Type 2 DM commence many years before the manifestation of clinical symptoms. The American Diabetes Association advocates for the screening of Type 2 DM in all asymptomatic individuals aged ≥ 45 years, utilizing fasting plasma glucose as the diagnostic criterion. In instances where fasting plasma glucose registers as normal (i.e., < 100 mg/dl), the screening test should be repeated at three-year intervals.

An alternative strategy involves selective screening, wherein individuals at a heightened risk of developing Type 2 Diabetes Mellitus (DM) are targeted. This includes those with one or more of the following risk factors: obesity (body mass index ≥ 25.0 kg/m2), a family history of DM (first-degree relative with DM), belonging to a high-risk ethnic group, hypertension, dyslipidemia, impaired fasting glucose, impaired glucose tolerance, or a history of Gestational Diabetes Mellitus (GDM). In such instances, screening is initiated at an earlier age, typically 30 years, and is conducted more frequently.

The recommended screening test for Type 2 DM is fasting plasma glucose. If the result is ≥126 mg/dl, it is advised to repeat the test on a subsequent day for confirmation of the diagnosis. In cases where the result is <126 mg/dl, an Oral Glucose Tolerance Test (OGTT) is recommended if there is a strong clinical suspicion. A 2-hour post-glucose load value in the OGTT that registers ≥200 mg/dl is indicative of DM and warrants confirmation through repetition on a different day.

Screening for Type 1 Diabetes Mellitus (DM): Type 1 DM is typically identified soon after its onset due to its acute presentation and distinctive clinical features. As a result, there is no imperative need to conduct routine blood glucose screening for Type 1 DM. The detection of immunologic markers, as mentioned earlier, is not currently recommended as a method to identify individuals at risk for Type 1 DM.

Screening for Gestational Diabetes Mellitus (GDM): Detailed information is provided earlier under the section on Oral Glucose Tolerance Test (OGTT) in gestational diabetes mellitus.

Laboratory Tests to Assess Glycemic Control

There exists a clear correlation between the extent of blood glucose control in both Type 1 and Type 2 Diabetes Mellitus (DM) and the emergence of microangiopathic complications, specifically nephropathy, retinopathy, and neuropathy. Sustaining blood glucose levels as close to normal as feasible, commonly denoted as tight glycemic control, serves to diminish the risk of microvascular complications. Additionally, persistent elevation of blood glucose values in DM is linked to heightened cardiovascular mortality.

The following methods are employed to monitor the degree of glycemic control:

  • Regular assessment of glycated hemoglobin through periodic measurements to evaluate long-term control.
  • Daily self-monitoring of blood glucose for the evaluation of day-to-day or immediate control.

Glycated Hemoglobin (Glycosylated Hemoglobin, HbA1C)

Glycated hemoglobin refers to hemoglobin to which glucose is nonenzymatically and irreversibly attached. Its quantity is contingent upon both blood glucose levels and the lifespan of red blood cells.

The interaction follows the equation: Hemoglobin + Glucose ↔ Aldimine → Glycated hemoglobin

Plasma glucose readily traverses the membranes of red blood cells, continuously binding with hemoglobin throughout the lifespan of these cells, which is approximately 120 days. Consequently, a portion of hemoglobin within red blood cells normally exists in a glycated form. The concentration of glycated hemoglobin in the bloodstream is influenced by both blood glucose levels and the lifespan of red blood cells. Higher blood glucose concentrations result in increased glycation of hemoglobin. Once glycated, hemoglobin undergoes an irreversible transformation. The level of glycated hemoglobin reflects the average glucose level over the preceding 6-8 weeks, approximately 2 months. This measurement is expressed as a percentage of total hemoglobin, with normal values typically below 5%.

Several prospective studies have consistently shown that maintaining optimal blood glucose control significantly diminishes the incidence and advancement of microvascular complications—namely, retinopathy, nephropathy, and peripheral neuropathy—in individuals with diabetes mellitus. The average level of glycated hemoglobin is closely associated with the risk of developing these complications.

The terms glycated hemoglobin, glycosylated hemoglobin, glycohemoglobin, HbA1, and HbA1c are commonly used interchangeably in clinical practice, denoting hemoglobins with nonenzymatically added glucose residues, albeit with variations in the modifications. Predominantly, studies have focused on HbA1c.

Routinely measuring glycated hemoglobin is essential for both type 1 and type 2 diabetic patients at regular intervals to evaluate the extent of long-term glycemic control. Beyond reflecting mean glycemia over the preceding 120 days, glycated hemoglobin levels also align with the risk of developing chronic complications associated with Diabetes Mellitus (DM). In the context of DM, it is advisable to maintain glycated hemoglobin levels below 7%.

Box 1: Glycated hemoglobin
  • Hemoglobin A1C of 6% corresponds to mean serum glucose level of 135 mg/dl. With every rise of 1%, serum glucose increases by 35 mg/dl. Approximations are as follows:
    • Hb A1C 7%: 170 mg/dl
    • Hb A1C 8%: 205 mg/dl
    • Hb A1C 9%: 240 mg/dl
    • Hb A1C 10%: 275 mg/dl
    • Hb A1C 11%: 310 mg/dl
    • Hb A1C 12%: 345 mg/dl
  • Assesses long-term control of DM (thus indirectly confirming plasma glucose results or self-testing results).
  • Assesses whether treatment plan is working
  • Measurement of glycated hemoglobin does not replace measurement of day-to-day control by glucometer devices.

Artifactual outcomes in glycated hemoglobin testing may arise in conditions of diminished red cell survival (hemolysis), instances of blood loss, and certain hemoglobinopathies.

In the context of Diabetes Mellitus (DM), a glycated hemoglobin level below 7% warrants biannual measurements. Conversely, if the level exceeds 8%, more frequent assessments (every 3 months) are recommended, accompanied by potential adjustments in the treatment regimen.

Diverse methods, including chromatography, immunoassay, and agar gel electrophoresis, are employed for the measurement of glycated hemoglobin.

The pivotal role of glycated hemoglobin in the management of DM is underscored in Box 1.

Self-Monitoring of Blood Glucose (SMBG)

Individuals with diabetes receive instruction on the regular self-monitoring of their blood glucose levels. The widespread utilization of Self-Monitoring of Blood Glucose (SMBG) devices, such as portable glucose meters, has significantly enhanced the management of Diabetes Mellitus (DM). These devices empower diabetic individuals to monitor their blood glucose levels on a daily basis, facilitating adjustments to insulin dosage to maintain levels as close to normal as possible. SMBG devices measure capillary whole blood glucose extracted through a fingerprick, utilizing test strips that incorporate glucose oxidase or hexokinase. Some strips integrate a layer to exclude blood cells, allowing the measurement of glucose in plasma. However, it's essential to recognize that the pursuit of tight glycemic control introduces the risk of severe hypoglycemia, a risk mitigated by the daily use of SMBG devices.

SMBG devices may produce unreliable results at extremely high and low glucose levels. To ensure accuracy, it is imperative to periodically assess the glucometer's performance by comparing results with parallel venous plasma glucose measurements in the laboratory.

While portable glucose meters serve as invaluable tools for day-to-day self-monitoring by patients, in outpatient clinic settings by physicians, and for bedside monitoring of admitted patients by healthcare workers, their application for the diagnosis and population screening of DM is cautioned against. The lack of precision and variability in results among different meters impede their suitability for such purposes.

The objective of achieving meticulous glycemic control in individuals with Type 1 Diabetes Mellitus (DM) using insulin can be realized through the self-monitoring of blood glucose levels using portable blood glucose meters.

Glycosuria

Semiquantitative urine glucose testing for diabetes mellitus monitoring in a home setting is not advisable. This is primarily due to:

  1. Absence of Information on Blood Glucose Concentration Below Renal Threshold: Even if urine glucose is undetectable, it provides no insights into blood glucose concentrations below the variable renal threshold (typically around 180 mg/dl; lower in pregnancy at 140 mg/dl, higher in the elderly and long-standing diabetics, and variable in some normal individuals with a low threshold).
  2. Inability to Detect Hypoglycemia: Urinary glucose testing lacks the capacity to identify hypoglycemic episodes.
  3. Impact of Urinary Concentration: The concentration of glucose in urine is influenced by urinary concentration, rendering semiquantitative urine glucose testing less reliable.

Semiquantitative urine glucose testing for monitoring has now been supplanted by the more accurate self-testing facilitated by portable glucose meters.

Laboratory Tests to Assess Long-term Risks

Urinary Albumin Excretion

Diabetes mellitus stands as a primary contributor to renal failure, with diabetic nephropathy manifesting in approximately 20-30% of individuals diagnosed with either type 1 or type 2 DM. The progression of diabetic nephropathy unfolds through distinct stages, as illustrated in Figure 3. Concurrently, hypertension ensues along the nephropathic course, correlating with escalating albumin excretion. Research affirms that early detection of diabetic nephropathy, coupled with targeted interventions, significantly mitigates the progression of renal impairment. The foundational strategy for early diabetic nephropathy identification involves assessing urinary albumin excretion.

For all adult patients with DM, routine reagent strip tests for proteinuria should be periodically conducted. A positive result indicates the presence of overt proteinuria or clinical proteinuria, potentially signaling overt nephropathy. In such cases, quantifying albuminuria is imperative to tailor appropriate therapeutic strategies. In instances where the routine dipstick test for proteinuria yields a negative result, screening for microalbuminuria is recommended.

Evolution of diabetic nephropathy
Figure 3: Evolution of diabetic nephropathy. In 80% of patients with type 1 DM, microalbuminuria progresses in 10-15 years to overt nephropathy that is then followed in majority of cases by progressive fall in GFR and ultimately end-stage renal disease. Amongst patients with type 2 DM and microalbuminuria, 20-40% of patients progress to overt nephropathy, and about 20% of patients with overt nephropathy develop end-stage renal disease. Abbreviation: GFR: Glomerular filtration rate

The term 'microalbuminuria' denotes the urinary excretion of albumin falling below the detection threshold of routine dipstick testing but surpassing normal levels (30-300 mg/24 hrs, 20-200 μg/min, or 30-300 μg/mg of creatinine). The albumin excretion rate in this range lies between the parameters of normal (urinary albumin excretion < 30 mg/24 hours) and overt albuminuria (> 300 mg/24 hours). The significance of microalbuminuria in Diabetes Mellitus (DM) encompasses the following aspects:

  • Earliest Marker of Diabetic Nephropathy: Microalbuminuria serves as the earliest discernible marker of diabetic nephropathy, with the potential for reversibility during the early stages of the condition.
  • Risk Factor for Cardiovascular Disease: It represents a risk factor for cardiovascular disease in both type 1 and type 2 diabetic patients.
  • Association with Blood Pressure and Glycemic Control: Microalbuminuria is linked to elevated blood pressure levels and suboptimal glycemic control.

Targeted therapeutic interventions, such as meticulous glycemic control, the administration of ACE (angiotensin-converting enzyme) inhibitors, and assertive management of hypertension, play a pivotal role in significantly decelerating the progression of diabetic nephropathy.

In the case of type 2 Diabetes Mellitus (DM), the initiation of microalbuminuria screening is recommended at the time of diagnosis. Conversely, for type 1 DM, this screening should commence 5 years after the initial diagnosis. During this assessment, a routine reagent strip test for proteinuria is conducted; if the result is negative, subsequent testing for microalbuminuria is performed. Subsequently, for patients with negative findings, periodic screening for microalbuminuria is advised on an annual basis.

Screening tests for microalbuminuria encompass:

There are reagent strip tests designed for the identification of microalbuminuria. Affirmative outcomes from these tests necessitate validation through more precise quantitative methods, such as radioimmunoassay and enzyme immunoassay. To establish the diagnosis of microalbuminuria, positive test results should be consistent across at least two out of three distinct samples obtained over a 3 to 6 month duration.

Lipid Profile

Disruptions in lipid profiles are linked to an elevated risk of coronary artery disease (CAD) in individuals with Diabetes Mellitus (DM). The mitigation of this risk can be achieved through the intensive treatment of lipid irregularities. Essential lipid parameters that merit measurement encompass:

  • Total cholesterol
  • Triglycerides
  • Low-density lipoprotein (LDL) cholesterol
  • High-density lipoprotein (HDL) cholesterol

The prevailing lipid aberrations in type 2 DM typically manifest as heightened triglyceride levels, diminished HDL cholesterol, and an increased proportion of small, dense LDL particles. Individuals with DM are stratified into high, intermediate, and low-risk categories based on their blood lipid levels (refer to Table 2).

Table 2: Categorization of cardiovascular risk in diabetes mellitus according to lipid levels (American Diabetes Association)
CategoryLow density lipoproteinsHigh density lipoproteinsTriglycerides
High-risk ≥130
  • < 35 (men)
  • < 45 (women)
≥ 400
Intermediate risk 100-129 35-45 200-399
Low-risk < 100
  • > 45 (men)
  • > 55 (women)
< 200

An annual assessment of the lipid profile is recommended for all adult patients diagnosed with Diabetes Mellitus.

Laboratory Tests in the Management of Acute Metabolic Complications of Diabetes Mellitus

The three most critical acute metabolic complications associated with Diabetes Mellitus (DM) are:

  • Diabetic ketoacidosis (DKA)
  • Hyperosmolar hyperglycemic state (HHS)
  • Hypoglycemia

DKA is characterized by hyperglycemia, ketosis, and acidosis. Common triggers for DKA include infection, noncompliance with insulin therapy, alcohol abuse, and myocardial infarction. Patients experiencing DKA typically present with rapid-onset polyuria, polydipsia, polyphagia, weakness, vomiting, and sometimes abdominal pain. Clinical signs encompass Kussmaul’s respiration, a fruity odor of acetone on breath, mental clouding, and dehydration. While DKA is classically associated with type 1 DM, HHS is more typical of type 2 DM. However, it's important to note that both complications can occur in either type. If left untreated, both DKA and HHS can progress to coma and result in fatality.

Hyperosmolar hyperglycemic state is distinguished by markedly elevated blood glucose levels (> 600 mg/dl), hyperosmolality (>320 mOsmol/kg of water), dehydration, absence of ketoacidosis, and altered mental status. This condition predominantly affects elderly individuals with type 2 diabetes. In HHS, insulin secretion is sufficient to prevent ketosis but not hyperglycemia. Causative factors for HHS include illness, dehydration, surgery, and glucocorticoid therapy.

The distinctions between DKA and HHS are summarized in Table 3.

Table 3: Comparison of diabetic ketoacidosis and hyperosmolar hyperglycemic state
ParameterDiabetic ketoacidosisHyperosmolar hyperglycemic state
Type of DM in which more common Type 1 Type 2
Age Younger age Older age
Prodromal clinical features < 24 hrs Several days
Abdominal pain, Kussmaul’s respiration Yes No
Acidosis Moderate/Severe Absent
Plasma glucose > 250 mg/dl Very high (>600 mg/dl)
Serum bicarbonate <15 mEq/L >15 mEq/L
Blood/urine ketones ++++ ±
β-hydroxybutyrate High Normal or raised
Arterial blood pH Low (<7.30) Normal (>7.30)
Effective serum osmolality* Variable Increased (>320)
Anion gap** >12 Variable
  • Osmolality: Number of dissolved (solute) particles in solution; normal: 275-295 mOsmol/kg
  • ** Anion gap: Difference between sodium and sum of chloride and bicarbonate in plasma; normal average value is 12

Laboratory assessment encompasses the following investigations:

  • Blood and urine glucose
  • Blood and urine ketones
  • Arterial pH, Blood gases
  • Serum electrolytes (sodium, potassium, chloride, bicarbonate)
  • Blood osmolality
  • Serum creatinine and blood urea

Testing for ketone bodies: Ketone bodies, including acetoacetic acid, acetone, and β-hydroxybutyric acid, result from the metabolism of free fatty acids.

Indications for ketone body testing in Diabetes Mellitus include:

  • At the time of diabetes mellitus diagnosis
  • At regular intervals for all known diabetes cases, during pregnancy with pre-existing diabetes, and in gestational diabetes
  • In known diabetic patients: during acute illness, persistent hyperglycemia (> 300 mg/dl), pregnancy, and clinical evidence of diabetic acidosis (nausea, vomiting, abdominal pain)

An elevated concentration of ketone bodies in DM patients signals impending or established diabetic ketoacidosis, constituting a medical emergency. A colorimetric reaction between ketone bodies and nitroprusside (via dipstick or tablet) is the method used for detecting both blood and urine ketones.

However, the test for urine ketones alone is not recommended for diagnosing and monitoring diabetic ketoacidosis. The measurement of β-hydroxybutyric acid, representing 75% of all ketones in ketoacidosis, is advised for diagnosis and monitoring of DKA.

Reference Ranges

  1. Venous plasma glucose:
    • Fasting: 60-100 mg/dl
    • At 2 hours in OGTT (75 gm glucose): <140 mg/dl
  2. Glycated hemoglobin: 4-6% of total hemoglobin
  3. Lipid profile:
    • Serum cholesterol: Desirable level: <200 mg/dl
    • Serum triglycerides: Desirable level: <150 mg/dl
    • HDL cholesterol: ≥60 mg/dl
    • LDL cholesterol: <130 mg/dl
    • LDL/HDL ratio: 0.5-3.0
  4. C-peptide: 0.78-1.89 ng/ml
  5. Arterial pH: 7.35-7.45
  6. Serum or plasma osmolality: 275-295 mOsm/kg of water.
    • Serum osmolality can be computed using the formula endorsed by the American Diabetes Association: Effective serum osmolality (mOsm/kg) = (2 × sodium mEq/L) + Plasma glucose (mg/dl) / 18
  7. Anion gap:
    • Na+ – (Cl + HCO3): 8-16 mmol/L (Average 12)
    • (Na+ + K+) – (Cl + HCO3): 10-20 mmol/L (Average 16)
  8. Serum sodium: 135-145 mEq/L
  9. Serum potassium: 3.5-5.0 mEq/L
  10. Serum chloride: 100-108 mEq/L
  11. Serum bicarbonate: 24-30 mEq/L

Critical Values

  1. Venous plasma glucose: > 450 mg/dl
  2. Strongly positive test for glucose and ketones in urine
  3. Arterial pH: < 7.2 or > 7.6
  4. Serum sodium: < 120 mEq/L or > 160 mEq/L
  5. Serum potassium: < 2.8 mEq/L or > 6.2 mEq/L
  6. Serum bicarbonate: < 10 mEq/L or > 40 mEq/L
  7. Serum chloride: < 80 mEq/L or > 115 mEq/L

References

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