Carbohydrate metabolism in obese individuals: insulin resistance and impaired glucose utilization

I. Carbohydrate Metabolism in Obesity

Obesity and altered carbohydrate metabolism: Metabolic disorders are one of the most significant pathophysiological changes in obese individuals and a major risk factor for many chronic diseases. Elevated free fatty acids (FFAs) in the blood of obese individuals is a central event in obesity-related metabolic disorders. Dysfunction of adipocytes prevents the timely oxidation of FFAs, leading to excessive FFAs entering the liver directly through the portal circulation, resulting in increased hepatic lipogenesis, gluconeogenesis, and insulin resistance (IR). Conversely, the IR state of adipocytes does not effectively inhibit lipolysis, thus increasing the secretion of free fatty acids. Furthermore, elevated leptin levels and decreased adiponectin levels in the blood reflect the metabolic characteristics of progressive IR. Glycerol-3-phosphate dehydrogenase (GPDH) participates in the esterification of fatty acids during metabolism, while glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme in the production of lipid synthesis substrates from glucose metabolism. These enzymes are regulated by dietary components and hormonal status. When consumed on a high-sugar and high-saturated-fat diet, elevated plasma insulin levels promote enzyme gene expression, while glucagon inhibits it. In vitro cell culture studies revealed that the expression of these enzyme genes in the adipocytes of obese rats was significantly enhanced compared to non-obese rats, indicating that abnormal expression of these genetically related enzyme genes is one of the causes of excessive fat accumulation.

Studies on obesity and insulin resistance have shown that insulin sensitivity varies greatly among individuals, but insulin resistance (IR) is often associated with obesity, especially in patients with significant increases in abdominal fat. Because IR is very common in morbidly obese individuals (BMI > 40 kg/m²), some researchers have suggested that IR may be an adaptive response to obesity, limiting further fat deposition. Differences in insulin resistance in specific organs or tissues may be the cause of localized fat accumulation. Obesity-related IR is initially thought to result from decreased receptor affinity or a reduced number of receptors, subsequently causing defects in the insulin signaling cascade in target organs such as the liver, adipose tissue, and skeletal muscle. Another central mechanism associated with IR is low-grade inflammation at IR levels, particularly cytokines such as tumor necrosis factor-α, which induce increased triglyceride (TG) hydrolysis and impaired gene expression involved in insulin signaling and adipocyte differentiation. The classic hyperinsulinemia clamp technique maintains a constant blood glucose level by altering the glucose infusion rate/volume to balance the biological effects of constant hyperinsulinemia. Glucose requirement is an indicator of insulin sensitivity, and conversely, it is an indicator of IR. Studies have shown that insulin resistance (IR) in skeletal muscle is a characteristic of obesity. Under induced hyperinsulinemia, skeletal muscle may account for 70%–90% of the total intravenous glucose transport, while the liver, intestines, and adipose tissue account for only a very small proportion of glucose uptake. Systemic IR primarily reflects muscle IR, which is significantly associated with excessive fat deposition and has been shown to be the earliest predictor of type 2 diabetes. In fact, the concentrated accumulation of body fat is related to IR. Under IR, a series of abnormal glucose metabolism occur, including impaired glucose oxidative clearance in skeletal muscle and reduced glycogen synthesis; increased glucose uptake in adipose tissue and liver can both lead to increased lipid synthesis. Secondly, IR enhances lipid oxidation, leading to excessive release of fatty acids (FFAs), thus exacerbating lipid metabolism disorders.

Obesity and Hyperinsulinemia: Excessive calorie and sugar intake, coupled with insufficient physical activity, are major causes of obesity. All three can increase insulin secretion, leading to hyperinsulinemia. Hyperinsulinemia is a key characteristic of obesity. Excessive insulin secretion is a significant contributing factor to obesity. One study showed that participants were on average 31.5% over their ideal weight, indicating that their calorie intake (mainly carbohydrates) exceeded their energy expenditure, and they experienced prolonged hyperinsulinemia after a glucose load, remaining in a hyperinsulin state for a considerable portion of the day. Under the stimulation of elevated insulin, the liver's utilization of various substrates, primarily glucose, for fat synthesis is enhanced, leading to increased synthesis and release of very low-density lipoprotein cholesterol (VLDL), resulting in elevated blood VLDL and triglyceride (TG) levels. Under the influence of hyperinsulinemia, adipose tissue experiences adipocyte proliferation, increased triglyceride synthesis and storage, and enlarged adipocytes, leading to weight gain and obesity. Muscle tissue, under the influence of hyperinsulinemia, also experiences increased glucose uptake and utilization. The presence of persistent hyperinsulinemia reduces the sensitivity of certain target tissues, such as muscle and fibroblasts, to insulin. This leads to decreased glucose uptake and oxidation in these tissues, resulting in a prolonged postprandial glucose decline and reduced glucose tolerance. However, with a significant decline in glucose tolerance and the progression of hyperinsulinemia, serum FFA levels decrease significantly after a glucose load, indicating that the response of adipose tissue to glucose and insulin has returned to normal, signifying the stable phase of obesity. At this point, target tissues such as muscle also develop insulin resistance. Research data also shows that skeletal muscle insulin resistance precedes hepatic insulin resistance, and increased postprandial hepatic triglyceride (TG) synthesis makes individuals with insulin resistance more susceptible to nonalcoholic fatty liver disease (NAFLD). Some researchers have found that ghrelin levels are reduced in obese individuals, and their blood levels are negatively correlated with both the degree of insulin resistance and hyperinsulinemia. Furthermore, the effects of insulin resistance and hyperinsulinemia on ghrelin levels are independent of BMI.