Section 2: Diagnostic Criteria and Classification of Diabetes

Based on susceptibility, insulin resistance is caused by defects in the insulin receptor and post-receptor signaling, as well as long-term combined effects of multiple factors such as overeating, obesity, and endocrine dysregulation of hepatic glycogen metabolism. Section 2: Diagnostic Criteria and Classification of Diabetes I. Clinical Manifestations Type 1 diabetes commonly occurs in adolescents, typically with an acute onset, obvious symptoms, and rapid progression. Without timely diagnosis and treatment, or in cases complicated by infection, patients are prone to diabetic ketoacidosis, which can be life-threatening. Type 2 diabetes mostly affects middle-aged and elderly individuals, with a slow onset; patients often have no subjective symptoms and are incidentally discovered during health check-ups or when seeking treatment for other conditions. Over many years after onset, some patients may remain asymptomatic, or only exhibit increased thirst and slightly more frequent urination, so they often do not pay attention in the early stages. However, as the disease progresses over the long term and hyperglycemia remains uncontrolled, various chronic complications may develop, including cardiovascular and cerebrovascular diseases such as coronary heart disease, myocardial infarction, cerebral hemorrhage, and cerebral infarction, as well as hypertension, retinal lesions causing blurred vision or blindness, diabetic nephropathy leading to edema, anemia, and uremia, diabetic neuropathy causing limb numbness, pain, infections, and necrosis, potentially resulting in disability or even death. During the prolonged course of diabetes, acute complications such as diabetic ketoacidosis, hyperosmolar coma, and hypoglycemia may also occur due to sudden triggers like acute infection, trauma, psychological stress, fatigue, or dietary imbalance. If these are not treated promptly and effectively, they can seriously endanger the patient's life. Therefore, for the relatively common type 2 diabetes, early detection and timely treatment are crucial. Regular diagnostic screening should be conducted for the following populations: ① age ≥45 years; ② obesity, with body weight exceeding standard weight by 20%; ③ first-degree relatives of diabetic patients; ④ those who have delivered a macrosomic infant (birth weight >4 kg) or have a history of gestational diabetes; ⑤ hypertensive patients (blood pressure ≥18.7/12 kPa); ⑥ patients with hyperlipidemia (TG ≥1.69 mmol/L and/or HDL-C ≤1.1 mmol/L). II. Laboratory Diagnosis (1) Urine Glucose Testing Normal individuals may have trace amounts of glucose in their urine, with approximately 32–93 mg of glucose excreted in 24 hours, which tests negative in routine urinalysis. Only when 24-hour urinary glucose exceeds 150 mg does qualitative urine glucose testing become positive. The appearance of positive urine glucose is related to blood glucose levels, glomerular filtration rate, and proximal renal tubule reabsorption of glucose. When renal function is normal, if blood glucose exceeds 8.9–10 mmol/L, urine glucose becomes positive; this blood glucose level is referred to as the renal threshold for glucose. However, not all individuals with positive urine glucose are diabetic; several other conditions that easily cause glycosuria should also be considered. ① Gestational glycosuria: During pregnancy, increased extracellular fluid volume inhibits the proximal renal tubules' ability to reabsorb glucose, lowering the renal threshold for glucose and resulting in gestational glycosuria. This phenomenon occurs only during pregnancy and returns to normal after delivery. ② Renal glycosuria: In renal glycosuria, blood glucose is normal, but the renal threshold for glucose is lowered, leading to positive urine glucose. It is often caused by congenital renal tubular defects, such as familial renal glycosuria; additionally, in Fanconi syndrome, renal tubular acidosis, and chronic nephritis, renal tubular damage can also lower the renal threshold for glucose, resulting in positive urine glucose. ③ Nutritional glycosuria: A small number of healthy individuals may experience temporary glycosuria after consuming large amounts of sweets, as excessive sugar absorption in the small intestine overloads the pancreas. (2) Blood Glucose Testing In healthy individuals, blood glucose remains relatively stable whether fasting or postprandial, generally ranging from 3.92 to 6.11 mmol/L when fasting. So how does the body regulate blood glucose stability? The body has factors that raise blood glucose, such as glucagon, epinephrine, cortisol, growth hormone, and sympathetic nervous system activation (during excitement or intense physical activity); at the same time, there are also factors that lower blood glucose, such as insulin and physical activity. Under normal circumstances, these two opposing forces are mutually regulated by the nervous system, maintaining relative balance and keeping blood glucose within the normal range. Fasting blood glucose is usually measured after a 10–12 hour fast starting from dinner the night before the test (water is allowed), with blood drawn between 6:00 and 8:00 the next morning. [Before blood draw, the subject should]{.underline} maintain emotional stability and avoid exercise[; and]{.underline} discontinue[the week before]{.underline} medications that can elevate blood glucose, such as oral contraceptives, prednisone, estrogen, niacin, etc. For those whose fasting blood glucose is above the normal range but does not meet the diagnostic criteria for diabetes (≥6.11 mmol/L and <7.0 mmol/L), or whose fasting blood glucose is normal but suspected of having diabetes, a glucose tolerance test can be performed; clinically, the oral glucose tolerance test (OGTT) is commonly used. Test procedure: ① On the day of the test, draw blood once while fasting in the morning, measure blood glucose, and collect urine for glucose testing; ② Immediately after fasting blood draw, orally ingest 75 g of glucose or eat 100 g of steamed bun, then start timing; ③ Draw blood and test glucose at 0.5 h, 1 h, 2 h, and 3 h post-meal, simultaneously collecting urine for glucose testing, to assess the renal threshold for glucose. Normally, fasting blood glucose does not exceed 6.11 mmol/L; 0.5 to 1 hour after meal, blood glucose concentration peaks, generally not exceeding 9.4 mmol/L, and urine glucose is negative. In diabetic patients, however, the blood glucose peak continues to rise, accompanied by positive urine glucose. By 2 hours post-meal, blood glucose level is <7.8 mmol/L, and by 3 hours it drops back to fasting levels, with urine glucose remaining negative. Diabetic patients experience a slow decline in blood glucose over 2–3 hours, and in some cases, even by 3 hours, blood glucose has not yet returned to normal levels. The oral glucose tolerance test (OGTT) is highly diagnostic for patients suspected of having diabetes; however, if fasting blood glucose is significantly higher than normal and urine glucose is positive, the diagnosis of diabetes can already be confirmed, making further glucose tolerance testing unnecessary. (3) Blood Insulin Levels and Insulin Release Test Insulin is an endocrine hormone secreted by the β cells of the pancreatic islets, playing a role in human carbohydrate metabolism and lowering blood glucose. Impaired function of pancreatic β cells is a major cause of diabetes; therefore, measuring blood insulin levels can reveal the reserve capacity of pancreatic β cells and help determine the subtype of diabetes. Normal fasting insulin levels are <30 μu/ml, rising to 50–150 μu/ml after eating. The insulin release test is usually performed using radioimmunoassay to measure blood insulin levels, and can be conducted concurrently with glucose tolerance testing—each time blood glucose is measured, insulin levels are also assessed (normal reference values are shown in Table 1). Table 1: Normal Reference Values for Insulin Release Test (M±SD μu/ml)

| > Fasting | > Postprandial | > 1 hour post-meal | > 2 hours post-meal | > 3 hours post-meal

Measured Value | 12.7±7. | > 1. | > 71.6±33.8 | > 46.9±26.7 | > 14.9±9.9 In healthy individuals, as blood glucose rises after eating, insulin secretion also increases accordingly, keeping blood glucose levels consistently within the normal range. In type 1 diabetic patients, due to β-cell dysfunction, fasting insulin levels are lower than normal. After oral glucose stimulation, insulin secretion decreases and fails to increase in proportion to rising blood glucose, with no peak secretion; or the peak secretion does not occur at 0.5–1 hour post-meal, but is delayed until 1–2 hours post-meal, and even the peak secretion does not reach normal levels. The former is called insufficient insulin secretion, seen in type 1 diabetes; the latter is called delayed insulin secretion, seen in type 2 diabetes patients. In the early stages of type 2 diabetes, most patients are obese, with fasting insulin levels normal or above normal; after oral glucose testing, most patients exhibit high insulin secretion peaks delayed until 2 hours post-meal, and insulin secretion levels are significantly higher than normal, termed delayed insulin secretion type. In contrast, for thin type 2 diabetic patients, fasting insulin levels are slightly below normal; after oral glucose testing, insulin secretion decreases, with peaks lower than normal and delayed until 2 hours post-meal, termed low-delayed insulin secretion type. (4) Serum C-peptide (C-P) Measurement C-peptide is also a product secreted by pancreatic β cells. Before pancreatic β cells secrete insulin, they first synthesize a substance called proinsulin; during insulin secretion, proinsulin is cleaved by enzymes to remove the connecting peptide C-peptide, becoming insulin. C-peptide has no physiological effect in the body; after entering the liver via the portal vein, it is not broken down by the liver, with a half-life of 11.1 minutes in the systemic circulation—more than twice the 4.8-minute half-life of insulin. Therefore, measuring C-peptide levels can more accurately reflect the β cells' ability to synthesize and secrete insulin. Moreover, for patients already receiving insulin therapy, the body may produce insulin antibodies, affecting insulin measurements. At the same time, the current radioimmunoassay method for measuring insulin cannot distinguish between insulin secreted by the body and insulin injected into the body, posing certain difficulties in assessing β-cell function. In contrast, C-peptide maintains a relatively constant ratio with insulin and is not affected by insulin antibodies, so measuring serum C-peptide levels can more accurately evaluate the β cells' synthesis and secretion of insulin. The C-peptide release test can be conducted concurrently with glucose tolerance testing, measuring both blood glucose and insulin/C-peptide levels (normal reference values are shown in Table 2). Table 2: Normal Reference Values for Oral Glucose (75 g) C-P Release Test (pmol/ml)

Fasting | > After Oral 75 g Glucose +-----------------+-----------------+-----------------+ | > 1 hour | > 2 hours | > 3 hours 0.38±0.15 | > 1.38±0.47 | > 1.06±0.58 | > 0.52±0.25 Type 1 diabetic patients exhibit low or no response in fasting C-P levels and after oral glucose stimulation, indicating poor β-cell secretion function; type 2 diabetic patients may have normal or above-normal fasting C-peptide levels, with high secretion levels after oral glucose, but the secretion peak is often delayed until 2 hours post-meal, suggesting hyperinsulinemia and primarily insulin resistance. (5) Serum Glucagon Measurement Sixty percent of the human pancreas consists of β cells, which secrete insulin, while the remaining 40% comprises α cells, δ cells, pancreatic polypeptide cells (PP), and enterochromaffin cells (Ec), respectively producing glucagon, somatostatin, pancreatic polypeptide, and serotonin. According to research reports, type 1 diabetic patients have almost no β cells in their pancreas, whereas type 2 diabetic patients have the same number of β cells as normal individuals, but significantly more α cells. Therefore, type 1 diabetic patients secrete very little or no insulin, while the concentration of glucagon secreted by α cells in the blood increases; in type 2 diabetic patients, due to insulin resistance, insulin is relatively scarce, and excessive glucagon secretion by α cells can exacerbate hyperglycemia and ketoacidosis. Thus, measuring blood glucagon levels helps better assess the condition and effectively guide treatment. The normal reference range for fasting glucagon is 70–120 pg/ml. (6) Glycated Hemoglobin and Fructosamine Measurement Glycated hemoglobin is the product of glucose combining with hemoglobin in red blood cells; the amount of glycated hemoglobin depends on the level of glucose in the blood—higher blood glucose means higher glycated hemoglobin. Since blood glucose measurement through blood draw only reflects the instantaneous glucose level, while human blood glucose levels fluctuate continuously throughout the day with meals, glycated hemoglobin is the product of glucose and hemoglobin slowly and irreversibly bonding via covalent bonds, and this bond does not require enzymatic catalysis—once formed, it does not dissociate. Red blood cells have a lifespan of 120 days, and during this period, the reaction constantly occurs, with its rate proportional to blood glucose concentration. Therefore, measuring glycated hemoglobin levels can reflect [the overall blood glucose level over the previous 1–2 months, serving as a good indicator for evaluating]{.underline} the effectiveness of diabetes control, unaffected by temporary fluctuations in blood glucose. Most laboratories use affinity chromatography to measure glycated hemoglobin, with a normal reference value of 5.8±0.9%. Fructosamine is the product of non-enzymatic slow glycation between serum albumin and glucose, forming glycated albumin; since serum albumin has a half-life of 1–3 weeks, measuring fructosamine levels can reflect the state of blood glucose control over the previous 1–4 weeks, and the measurement method is relatively simple with fairly accurate results[.]{.underline} The normal reference value for serum fructosamine is 2.14±0.25 mmol/L. III. Diagnostic Criteria Diagnosing diabetes solely based on the common "three polys and one less" symptoms, along with urine glucose and fasting blood glucose tests, is no longer sufficient. This is because most cases of diabetes have a slow onset, with early-stage patients often showing no obvious symptoms, and the appearance of urine glucose and elevated fasting blood glucose can also be caused by other factors. Therefore, a unified standard is needed for diagnosing diabetes. Currently, the clinical diagnostic criteria for diabetes were recommended by the World Health Organization (WHO) in 1980 and revised by the WHO Diabetes Research Group in 1985. Over the past decade and more, research on diabetes has made significant progress in areas such as etiology, pathogenesis, epidemiology, and prevention and control, rendering the original diagnostic criteria and classification inadequate for new situations. Consequently, in December 1996, the WHO convened a meeting in the United Kingdom to discuss diagnostic criteria and classification for diabetes and its complications, and put forward preliminary recommendations and drafts. Based on this, in 1997, the American Diabetes Association (ADA) formally published a report proposing the following revisions to the diagnostic criteria and classification for diabetes. Table 3: Thresholds for Different Blood Glucose States

State | > FPG (Fasting Plasma Glucose) | > .OGTT 2h (Oral Glucose Tolerance Test) | | > | | > 2h plasma glucose in the test) Normal, | > <6.11 mmol/L | > <7.8 mmol/L IFG | > ≥6.11 mmol/L and <7.0 mmol/L | | | (Fasting Glucose Tolerance Reduced) | | IGT | | > ≥7.8 mmol/L | | (Oral Glucose Tolerance Reduced) | | Diabetes | > ≥7.0 mmol/L | > ≥11.1 mmol/L Note: IFG: According to epidemiological studies, individuals with fasting blood glucose ≥6.11 mmol/L and <7.0 mmol/L have risk factors for large-vessel damage, such as hypertension, high triglycerides (TG), and reduced high-density lipoprotein (HDL-C), so the concept of reduced fasting glucose tolerance (IFG) was proposed, which is beneficial for preventing cardiovascular and cerebrovascular diseases.

Table 4: Revised Diagnostic Criteria for Diabetes

1. Diabetes symptoms + random-time plasma glucose ≥11.1 mmol/L; Random time refers to any time of the day. Diabetes symptoms include polyuria, polydipsia, and unexplained weight loss.
2. Fasting plasma glucose ≥7.0 mmol/L; fasting means at least 8 hours without caloric intake. 3.75 g glucose OGTT 2h plasma glucose ≥11.1 mmol/L