Main Menu

Complications of Diabetes Mellitus (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 it also occurs in individuals who lack immunologic features of type 1 DM and who can subsequently be treated with oral glucose-lowering agents (these obese individuals with type 2 DM are often of Hispanic or African-American descent). HHS is primarily seen in individuals with type 2 DM. Both disorders are associated with absolute or relative insulin deficiency, volume depletion, and acid-base abnormalities. DKA and HHS exist along a continuum of hyperglycemia, with or without ketosis. Both disorders are associated with potentially serious complications if not promptly diagnosed and treated.

1) Diabetic Keto- acidosis

Diabetic Ketoacidosis (DKA) is a state of inadequate insulin levels resulting in high blood sugar and accumulation of organic acids and ketones in the blood. It is a potentially life-threatening complication in patients with diabetes mellitus. It happens predominantly in type 1 diabetes mellitus, but it can also occur in type 2 diabetes mellitus under certain circumstances.


DKA most frequently occurs in known diabetics. It may also be the first presentation in patients who had not previously been diagnosed as diabetics. There is often a particular underlying problem that has led to the DKA episode. This may be intercurrent illness (pneumonia, influenza, gastroenteritis, a urinary tract infection), pregnancy, inadequate insulin administration (e.g. defective insulin pen device), myocardial infarction (heart attack), stroke or the use of cocaine. Young patients with recurrent episodes of DKA may have an underlying eating disorder, or may be using insufficient insulin for fear that it will cause weight gain. In 5% of cases, no cause for the DKA episode is found.

Diabetic ketoacidosis may occur in those previously known to have diabetes mellitus type 2 or in those who on further investigations turn out to have features of type 2 diabetes (e.g. obesity, strong family history); this is more common in African, African-American and Hispanic people. Their condition is then labeled “ketosis-prone type 2 diabetes“.


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.

The combination of insulin deficiency and hyperglycemia reduces the hepatic level of fructose-2,6-phosphate, which alters the activity of phosphofructokinase and fructose-1,6-bisphosphatase. Glucagon excess decreases the activity of pyruvate kinase, whereas insulin deficiency increases the activity of phosphoenolpyruvate carboxykinase. These changes shift the handling of pyruvate toward glucose synthesis and away from glycolysis. The increased levels of glucagon and catecholamines in the face of low insulin levels promote glycogenolysis. Insulin deficiency also reduces levels of the GLUT4 glucose transporter, which impairs glucose uptake into skeletal muscle and fat and reduces intracellular glucose metabolism

Normally, the free fatty acids released by adipolysis are converted to triglycerides or VLDL in the liver. However, in DKA, hyperglucagonemia alters hepatic metabolism to favor Ketone body formation, through activation of the enzyme carnitine palmitoyl Transferase I. This enzyme is crucial for regulating fatty acid transport into the mitochondria, where beta oxidation and conversion to ketone bodies occur.

The ketone bodies, however, have a low pH and therefore turn the blood acidic (metabolic acidosis). The body initially buffers this with the bicarbonate buffering system, but this is quickly overwhelmed and other mechanisms to compensate for the acidosis, such as hyperventilation to lower the blood carbon dioxide levels. This hyperventilation, in its extreme form, may be observed as Kussmaul respiration. Ketones, too, participate in osmotic diuresis and lead to further electrolyte losses. As a result of the above mechanisms, the average adult DKA patient has a total body water shortage of about 6 liters (or 100 ml/kg), in addition to substantial shortages in sodium, potassium, chloride, phosphate, magnesium and calcium. Glucose levels usually exceed 13.8 mmol/l or 250 mg/dl.

Increased lactic acid production also contributes to the acidosis. The increased free fatty acids increase triglyceride and VLDL production. VLDL clearance is also reduced because the activity of insulin-sensitive lipoprotein lipase in muscle and fat is decreased. Most commonly, DKA is precipitated by increased insulin requirements, as might occur during a concurrent illness. Occasionally, complete omission of insulin by the patient with type 1 DM precipitates DKA.

Clinical manifestations- The symptoms of an episode of diabetic ketoacidosis usually evolve over the period of about 24 hours. Predominant symptoms are nausea and vomiting, pronounced thirst, excessive urine production and abdominal pain that may be severe. Hyperglycemia is always present .In severe DKA, breathing becomes labored and of a deep, gasping character (a state referred to as “Kussmaul respiration“). The abdomen may be tender to the point that an acute abdomen may be suspected, such as acute pancreatitis, appendicitis or gastrointestinal perforation. Coffee ground vomiting (vomiting of altered blood) occurs in a minority of patients; this tends to originate from erosions of the esophagus. In severe DKA, there may be confusion, lethargy, stupor or even coma (a marked decrease in the level of consciousness).

On physical examination there is usually clinical evidence of dehydration, such as a dry mouth and decreased skin turgor. If the dehydration is profound enough to cause a decrease in the circulating blood volume, tachycardia (a fast heart rate) and low blood pressure may be observed. Often, a “ketotic” odor is present, which is often described as “fruity”. If Kussmaul respiration is present, this is reflected in an increased respiratory rate.

Small children with DKA are relatively prone to cerebral edema (swelling of the brain tissue), which may cause headache, coma, loss of the pupillary light reflex, and progress to death. It occurs in 0.7–1.0% of children with DKA, and has been described in young adults, but is overall very rare in adults. It carries 20–50% mortality.





















Figure- showing causes and consequences of DKA



Diabetic Ketoacidosis may be diagnosed when the combination of hyperglycemia (high blood sugars), ketones on urinalysis and acidosis are demonstrated. Arterial blood gas measurement is usually performed to demonstrate the acidosis; this requires taking a blood sample from an artery. In addition to the above, blood samples are usually taken to measure urea and creatinine (measures of kidney function, which may be impaired in DKA as a result of dehydration) and electrolytes. Furthermore, markers of infection (complete blood count, C-reactive protein) and acute pancreatitis (amylase and lipase) may be measured. Given the need to exclude infection, chest radiography and urinalysis are usually performed.

If cerebral edema is suspected because of confusion, recurrent vomiting or other symptoms, computed tomography may be performed to assess its severity and to exclude other causes such as stroke.


The main aims in the treatment of diabetic ketoacidosis are replacing the lost fluids and electrolytes while suppressing the high blood sugars and ketone production with insulin.

Fluid replacement– The amount of fluid depends on the estimated degree of dehydration. If dehydration is so severe, rapid infusion of saline is recommended to restore circulating volume.

Insulin is usually given continuously.

Potassium levels can fluctuate severely during the treatment of DKA, because insulin decreases potassium levels in the blood by redistributing it into cells. Serum potassium levels are initially often mildly raised even though total body potassium is depleted. Hypokalemia often follows treatment. This increases the risk of irregularities in the heart rate. Therefore, continuous observation of the heart rate is recommended, as well as repeated measurement of the potassium levels and addition of potassium to the intravenous fluids once levels fall below 5.3 mmol/l. If potassium levels fall below 3.3 mmol/l, insulin administration may need to be interrupted to allow correction of the hypokalemia.


Sodium bicarbonate solution is administered to rapidly improve the acid levels in the blood.

Cerebral edema– administration of fluids is slowed; intravenous Mannitol and hypertonic saline (3%) are used.

2) Hyperglycemic Hyperosmolar State (HHS)

Clinical Features-

HHS occurs in elderly individuals with type 2 DM, with a several week history of polyuria, weight loss, and diminished oral intake that culminates in mental confusion, lethargy, or coma.

The physical examination reveals-

  • Profound dehydration and hyperosmolality
  • Hypotension, tachycardia, and altered mental status.
  • Nausea, vomiting, abdominal pain and the Kussmaul respirations characteristic of DKA are absent.
  • 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.


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 completely understood. Presumably, the 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 in some studies. It is also possible that the liver is less capable of ketone body synthesis or that the insulin/glucagon ratio does not favor ketogenesis.

Laboratory Abnormalities and Diagnosis

Most notable are the marked hyperglycemia [plasma glucose may be >55.5 mmol/L (1000 mg/dL)], hyperosmolality (>350 mosmol/L), and prerenal azotemia. The measured serum sodium may be normal or slightly low despite the marked hyperglycemia. The corrected serum sodium is usually increased [add 1.6 meq to measured sodium for each 5.6-mmol/L (100 mg/dL) rise in the serum glucose]. In contrast to DKA, acidosis and ketonemia are absent or mild. A small anion gap metabolic acidosis may be present secondary to increased lactic acid. Moderate ketonuria, if present, is secondary to starvation.

Treatment-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 co morbidities. Even with proper treatment, HHS has a substantially higher mortality than DKA (up to 15% in some clinical series).

3) Lactic acidosis

Type 1 lactic acidosis occurs in hypoxic individuals and is due to an excessive production of lactate by peripheral tissues. Hypoxia is not a feature of lactic acidosis which occurs due to impaired metabolism of lactate in the liver. Both are characterized by extreme metabolic acidosis. There is high anion gap with low or absent ketones and high lactate levels.


Large amount of intravenous sodium bicarbonate is needed to correct the acidosis. Alternatively the patient may be dialyzed against a bicarbonate containing solution.


Please help "Biochemistry for Medics" by CLICKING ON THE ADVERTISEMENTS above!