Diabetes: Definition, Differential Diagnosis and Classification

Definitions

• Criteria for diabetes
  • diabetic-level fasting glucose concentration (fasting plasma glucose ≥ 7.0 mmol/l) OR
  • HbA_1c≥ 48 mmol/mol (6.5%) (check local requirements whether one or two abnormal results are required) OR
  • plasma glucose ≥ 11.1 mmol/l in a patient with symptoms, one measurement is sufficient (at any time of the day) OR
  • plasma glucose at 2 hours in oral glucose tolerance test ≥ 11.1 mmol/l.
• If there are no evident symptoms (continuous thirst, polyuria, weight loss), the diagnosis requires
  • 2 separate results exceeding the threshold value in different parameters or an abnormal result in one parameter on two different days.
  • HbA_1c≥ 48 mmol/mol (6.5%); one measurement may be sufficient in some countries, while the WHO and some other recommendations require 2 abnormal results.
• A 2-hour glucose tolerance test is not required if the diagnostic criteria are otherwise fulfilled.
• It is worthwhile to perform a 2-hour glucose tolerance test if fasting glucose level is slightly elevated (6.1-7.0 mmol/l), HbA_1c concentration is 42-47 mmol/mol (6-6.5%) or risk test score is above threshold (see e.g. http://www.mdcalc.com/findrisc-finnish-diabetes-risk-score).
• The risk of diabetes is increased in persons with elevated fasting glucose level or impaired glucose tolerance; see table T1 for threshold values.

• HbA_1c concentration < 48 mmol/mol (6.5%) does not exclude diabetes.
  • A shortened life span of red blood cells (e.g. bleeding, haemolysis, EPO therapy) leads to erroneously low concentrations, and in rapidly developing insulin deficiency the HbA_1c concentration has not necessarily had enough time to increase.
• After establishing the diagnosis of diabetes, always consider which type of diabetes it is.
• Unless the patient shows signs of type 1 diabetes (see below), the patient is most likely to have type 2 diabetes.
• The term type 2 diabetes usually refers to diabetes diagnosed in adulthood when the patient can survive without insulin and there are no ketone bodies in the urine or plasma. Type 2 diabetes is usually preceded by metabolic syndrome.
  • In 2019 it was estimated that the global prevalence of diabetes is over 9% (463 million people) and that type 2 diabetes accounts for about 90% of the total http://www.sciencedirect.com/science/article/pii/S0168822719312306.
• The age of onset is only suggestive of the type of diabetes. At diagnosis, 10-15% of patients with type 1 diabetes are over the age of 30 years. The so-called MODY (Maturity Onset Diabetes of Youth) type of diabetes often begins before the age of 30 years, as occasionally does type 2 diabetes.
• Some patients (approximately 10%) appear, initially, to have type 2 diabetes, but have GAD antibodies and half of them develop a significant insulin deficiency within a few years. These patients are classified as having slowly progressing type 1 diabetes. This condition is also referred to with the term LADA (Latent Autoimmune Diabetes in Adults). It is worthwhile to determine GAD antibodies if the patient is of normal weight or has significantly lost weight or is less than 30 to 40 years of age or if oral antidiabetic drugs or GLP-1 analogues do not work as they are expected to work.

Signs and symptoms suggestive of type 1 diabetes

• The patient is thin or of normal weight, but overweight does not, however, exclude type 1 diabetes.
• Unintentional weight loss
  • Significant unintentional weight loss during the few weeks preceding the diagnosis usually suggests insulin-dependent diabetes.
• Ketoacidosis
  • Serum ketone body concentration is increased when measured with a point-of-care (POC) meter from a finger-prick or venous blood sample. Urine ketone bodies (chemical dipstick screening test) should be determined if no blood measurement is available. Although ketone bodies may be found even in a healthy person during fasting or ketogenic diet, if they are found in the context of a fresh diabetes, the patient must be referred as an emergency case for further investigations.
  • Metabolic acidosis (low BE level and/or low pH in Astrup analysis)
• Low C-peptide concentration (i.e. endogenous insulin production impaired)
  • Serum C-peptide - low at the time of diagnosis (< 0.3-0.6 nmol/l during hyperglycaemia), later undetectable (usually < 0.1 nmol/l). Note! The C-peptide level result will not become available at the emergency department and it is dependent on the blood glucose level (increased with high glucose levels and decreased with low glucose levels).
• Increased concentration of glutamate decarboxylase (GAD) or IA2 antibodies (in children also anti-insulin antibodies). In patients over 20 years of age the primary test is GAD antibody assay and then IA2 antibodies (or islet cell antibodies) are determined if GAD antibodies are not present. If antibodies are not found (in 10-15% of patients with type 1 diabetes) and no complete insulin deficiency develops, the possibility of some other type of diabetes should be considered. The antibodies do not help in decision making in an emergency situation.
• Onset usually under the age of 30 years; however, in some patients (10-15%) the illness appears at a later stage.

Signs and symptoms suggestive of type 2 diabetes (ICD-10: E11)

• The most common type of diabetes
• 80% of the patients are overweight and they have insulin resistance syndrome (metabolic syndrome Metabolic Syndrome). Also a person with type 1 diabetes may have metabolic syndrome.
• Patients are often asymptomatic and type 2 diabetes is found within the follow-up of metabolic syndrome, IFG or IGT, or accidentally. Long-term hyperglycaemia and related glucosuria may cause inadvertent weight loss even in overweight patients; additionally, symptoms may include fatigue, urinary frequency and increased thirst.
• Usually diagnosed in adulthood.
• Atherosclerosis is the most significant complication of the illness, i.e. coronary heart disease, arteriopathies of the lower limbs and brain and other macrovascular diseases (stroke).
• Long-term hyperglycaemia causes retinopathy, nephtropathy and neuropathy, signs of which may exist already at the time of diabnosis of type 2 diabetes.
• Non-alcoholic fatty liver disease (NAFLD, in 50-70% of patients with type 2 diabetes) and its more serious forms non-alcoholic steatohepatitis (NASH Metabolic Dysfunction-Associated Steatotic Liver Disease (Masld) and Steatohepatitis (Mash)), fibrosis and hepatocellular carcinoma (HCC) are 2-4 times more common in patients with type 2 diabetes compared with persons with no diabetes.
• The patients often have a considerable family history of diabetes, hypertension and arterial diseases.
• Serum or urine ketone bodies should be determined when a fresh case of diabetes is suddenly found.
• Serum C-peptide concentration is determined if there is uncertainty about the type of diabetes. A very low concentration (below 0.2-0.3 nmol/l) strongly suggests insulin deficiency, in which case insulin therapy is required at least at the initial phase. Severe hyperglycaemia (> 15 mmol/l) may temporarily reduce the excretion of insulin. Redetermination of the C-peptide concentration after the hyperglycaemia has been corrected may be indicated to assess the further need of insulin therapy. An increased C-peptide concentration suggests insulin resistance.
• A glucose tolerance test should be performed if diagnostic criteria are not met.
  • Fasting plasma glucose is increased to level 6.1-7.0 mmol/l, or HbA_1C is 42-47 mmol/mol.
  • IGT can only be detected in the tolerance test; see table T1.

Other types of diabetes

• MODY (Maturity Onset Diabetes of Youth)
  • Can be confused with both type 1 and type 2 diabetes.
  • Includes several subtypes caused by mutations mainly in genes which regulate insulin secretion and/or development of the pancreas.
  • Typical features of MODY diabetes include
    • early onset (often < 25 years of age, large variation!)
    • dominant inheritance pattern (diabetes present in several generations - important to investigate other members of the family); lack of family history does not exclude MODY type diabetes if the suspicion is strong on other grounds (new mutations do develop)
    • impaired insulin response to glucose; some patients also have actual insulin deficiency; the severity degree of these abnormalities varies
    • an increased risk of hypoglycaemia in association with antidiabetic medication, in some patients also spontaneously and even before the diagnosis of diabetes.
  • Cystic kidney disease, increased concentrations of aminotransferases and/or urate, low magnesium concentration, as well as abnormalities of the genitals may be associated with HNF1B diabetes.
  • Some patients manage with a diet or oral medication while others may need multiple-injection regimes if insulin. The most common form, a glucokinase defect, usually requires no treatment. It presents as slightly elevated fasting blood glucose levels.
  • In the second most common form, the HNF1A diabetes, a high-carbohydrate meal increases blood glucose level quite strongly, even though the fasting blood glucose level might remain good for a long period.
  • If MODY is suspected, the patient should be referred to a diabetic clinic for gene testing and genetic counselling.
• Mitochondrial diabetes is a rare genetic defect, which is passed from the mother to the next generation (both males and females). Comorbidities include other organ changes, such as hearing defects, cardiomyopathy and neurological symptoms (MELAS syndrome http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=550). The severity of insulin deficiency varies.
• Secondary diabetes
  • Develops most commonly after pancreatitis Pancreatic Insufficiency. May also be associated with hypercorticoidism (glucocorticoid medication or Cushing's syndrome) or with over-secretion of growth hormone (acromegaly). The patients often have a positive family history of type 2 diabetes.
• Diabetes following pancreatectomy
  • Develops after complete pancreatectomy and is associated with a highly increased proneness to hypoglycaemia.

Gestational diabetes

• Disturbance of glucose metabolism associated with pregnancy (see Gestational Diabetes Mellitus (Gdm))
• 20-50% of patients will later develop type 2 diabetes, a small proportion will develop type 1 diabetes.