Synergistic effects of metabolic abnormalities: obesity combined with type 2 diabetes, gout, and metabolic syndrome

I. Overview Metabolism is a fundamental form of human life activity, comprising two processes: anabolism and catabolism. Abnormalities in any stage of the synthesis or catabolism of nutrients in the body can lead to disease, known as metabolic disease. Common metabolic diseases include obesity, diabetes, gout, lipid metabolism disorders, and metabolic syndrome. Obesity and metabolic diseases are closely related and often co-occur. Data from the 2010 Chinese Diabetes Epidemiological Survey showed that the prevalence of type 2 diabetes in overweight and obese individuals was 12.8% and 18.5%, respectively, and the prevalence gradually increased with increasing BMI. Among diabetic patients, the proportions of overweight, obese, and abdominally obese individuals (waist circumference ≥90cm for men, waist circumference ≥85cm for women) were 41%, 24.3%, and 45.4%, respectively. Studies have shown that the prevalence of hyperuricemia is 17.8% in individuals with a BMI <25 kg/m², while the prevalence is as high as 37.1% in individuals with a BMI >25 kg/m². Obesity significantly increases the risk of various metabolic diseases such as type 2 diabetes, dyslipidemia, and gout, resulting in a huge disease burden. Weight loss can improve insulin resistance and lower indicators such as blood glucose, blood lipids, and uric acid; within a certain range, the greater the weight loss, the greater the benefit. Obesity is not only a common metabolic disease but also a high-risk factor for metabolic diseases such as diabetes, dyslipidemia, and metabolic syndrome. Strengthening early intervention for obesity can effectively reduce the risk of developing metabolic diseases. II. Pathophysiological Changes

Insulin resistance and pancreatic β-cell dysfunction are the fundamental characteristics of type 2 diabetes. Obese individuals all exhibit insulin resistance, with visceral obesity and larger adipocytes being more prone to insulin resistance than peripheral obesity. In conjunction with genetic predisposition, long-term and severe insulin resistance ultimately leads to pancreatic β-cell dysfunction, causing a series of metabolic disorders.

Gout and obesity can lead to insulin resistance. Insulin acts directly on the proximal convoluted tubules of the kidneys, causing a decrease in the kidneys' clearance of uric acid and subsequently, elevated blood uric acid levels. Insulin resistance can activate the renin-angiotensin-aldosterone system, reducing renal blood flow and consequently decreasing uric acid excretion. Furthermore, obese individuals often consume more energy than they expend, leading to increased purine synthesis and uric acid production. There may be some shared genetic defects between hyperuricemia and obesity. Leptin may be an intermediary factor linking obesity and hyperuricemia; mutations in the leptin receptor lead to leptin resistance, causing obesity and hyperuricemia, while high uric acid levels stimulate the expression of obesity genes.

In obese patients, lipid metabolism abnormalities are related to insulin resistance and abnormal secretion of adipokines, leading to excessive production and reduced clearance of triglycerides (TG) and very low-density lipoprotein (VLDL), resulting in abnormal lipid metabolism. The main manifestations of abnormal lipid metabolism include elevated TG or hypertriglyceridemia, decreased HDL-c, elevated LDL-c, elevated LDL, and an elevated LDL/HDL ratio.

In metabolic syndrome, fat accumulation in pancreatic islet cells can lead to impaired secretory function of pancreatic β-cells. Fat accumulation in skeletal muscle and liver can cause insulin resistance, and excessive liver fat storage can lead to dyslipidemia. These pathophysiological changes may all be related to abnormal levels of free fatty acids and adipokines function. In obesity, the adipokines spectrum expressed in adipose tissue changes, manifested as elevated blood free fatty acids, increased PAI-1, hyperleptinemia, and decreased secretion of adiponectin, which improves insulin resistance. Numerous inflammatory cytokines activate inflammatory signaling pathways, collectively leading to insulin resistance and metabolic syndrome. III. Clinical Manifestations

Type 2 diabetes is the most common type of diabetes, and it can occur at any age, but is more common in middle-aged and elderly people, although there has been a trend of younger onset in recent years. Initial symptoms are varied; in addition to the typical "three highs and one low" (polyuria, polydipsia, polyphagia, and weight loss), itchy skin, decreased vision, and acute or chronic complications can all be initial manifestations. Some patients are asymptomatic in the early stages and are diagnosed during physical examinations or when seeking treatment for other diseases. Poorly controlled diabetes can lead to acute and chronic complications, resulting in symptoms of damage to corresponding systems. Acute complications include diabetic ketoacidosis, hyperosmolar nonketotic diabetic coma, lactic acidosis, and hypoglycemia; chronic complications include diabetic nephropathy, diabetic cerebrovascular disease, diabetic retinopathy, and diabetic foot.

Gout is a heterogeneous group of chronic metabolic diseases caused by purine metabolism disorders. It can occur at any age, but is more common in middle-aged and elderly people, and more prevalent in men than women. Obese individuals and those with low levels of physical activity are more susceptible to this disease. Clinical features include hyperuricemia, recurrent gouty arthritis, tophi, and interstitial nephritis. In severe cases, it can be accompanied by joint deformities or uric acid urinary tract stones. Acute arthritis is the most common initial symptom of gout, frequently affecting the first metatarsophalangeal joint. Other common sites of onset include the soles of the feet, ankles, knees, wrists, and elbows. Symptoms include waking up in the early morning due to joint pain, accompanied by localized heat, redness, swelling, and significant tenderness in the affected joint. Common triggers include overeating, hunger, alcohol abuse, excessive fructose intake, overwork, exposure to cold, surgery, and consumption of purine-rich foods. Chronic arthritis is more common in untreated or improperly treated patients. Tophi are a characteristic manifestation of chronic arthritis, commonly found in the auricle, metatarsophalangeal joints, interphalangeal joints, and elbows. When tophi rupture, white powdery urate crystals are released, and in severe cases, it can cause hand and foot deformities. Kidney disease is common in patients with a long disease course, manifesting as gouty nephropathy, uric acid nephrolithiasis, and acute renal failure.

Abnormal lipid metabolism can lead to the formation of xanthomas due to excessive lipid deposition in local tissues. These xanthomas manifest as localized skin protrusions, often nodules, papules, or plaques, and are soft in texture, typically yellow, orange-yellow, or brownish-red in color. In some patients, lipid deposition in the vascular endothelium can cause atherosclerosis, leading to coronary heart disease and cerebrovascular diseases. A small number of patients may develop pancreatitis due to chylomicrons blocking capillaries in the pancreas. While hyperlipidemia does not frequently cause xanthomas, and the development of atherosclerosis is a gradual process, most patients do not exhibit obvious symptoms or abnormal signs and are often diagnosed during physical examinations or blood biochemistry tests for other medical conditions.

Metabolic syndrome (MS) is a clinical condition characterized by multiple metabolic abnormalities in a single individual, including impaired glucose tolerance or diabetes, central obesity, dyslipidemia, and hypertension. Obesity is not only a component of MS but also a risk factor for other diseases within MS. Mild to moderate obesity is generally asymptomatic, while severe obesity may present with heat intolerance, decreased activity levels, shortness of breath during activity, and snoring during sleep. Significant weight gain over a short period can result in purple striae on the lower abdomen, thighs, and outer buttocks. In severely obese individuals, the skin on the armpits, buttocks, and inner thighs becomes thickened and wrinkled, resembling acanthosis nigricans. Furthermore, dyslipidemia and diabetes, as part of metabolic syndrome, often coexist with or occur sequentially with obesity.

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