Why do people get type 2 diabetes?

Dr. Roy Taylor’s Twin Cycle Hypothesis offers a unified explanation for how chronic excess energy intake gradually leads to the development of insulin resistance and, eventually, type 2 diabetes. At its core, this hypothesis explains that two interconnected “cycles”—one in the liver and one in the pancreas—drive the progressive deterioration in glucose control over many years.

The Role of Caloric Excess and Muscle Insulin Resistance
Our bodies are designed to store excess energy when we consistently consume more calories than we expend. In a healthy individual, skeletal muscle is a primary site for storing excess carbohydrates in the form of glycogen. However, many people have a degree of muscle insulin resistance that limits this storage capacity. Insulin resistance in muscle is not an abnormality in itself but exists as a spectrum in the general population. For individuals with relatively lower muscle insulin sensitivity, a larger fraction of dietary carbohydrates cannot be effectively stored in muscle, and these excess carbohydrates are diverted to the liver.

De Novo Lipogenesis and Liver Fat Accumulation
Once in the liver, the surplus carbohydrates are converted into fat through a process called de novo lipogenesis. Under normal conditions, this pathway operates at a modest rate. However, when there is a persistent caloric surplus, the liver begins to accumulate triglycerides. Insulin plays a dual role here: while it normally helps regulate blood sugar levels, chronically elevated insulin levels—as a compensatory mechanism for muscle insulin resistance—further stimulate de novo lipogenesis. Over time, this leads to an abnormal buildup of fat in the liver, a condition known as non-alcoholic fatty liver disease (NAFLD).

The accumulation of liver fat interferes with the liver’s normal response to insulin. In a healthy liver, insulin suppresses the production of glucose, maintaining stable fasting blood sugar levels. However, as fat accumulates, the liver becomes increasingly resistant to insulin’s actions. This hepatic insulin resistance means that even though insulin is present, the liver continues to produce and release glucose into the bloodstream, contributing to elevated fasting plasma glucose levels.

The Vicious Liver Cycle
This scenario sets up a vicious cycle in the liver. As liver fat increases, so does hepatic insulin resistance. The resulting higher fasting glucose levels drive the pancreas to secrete more insulin to compensate. In turn, the elevated insulin levels further stimulate de novo lipogenesis, causing even more liver fat accumulation. This self-reinforcing “liver cycle” gradually pushes the metabolic state closer to overt diabetes, even though blood glucose levels may remain near normal for many years due to compensatory hyperinsulinemia.

Spill-Over to the Pancreas and Beta Cell Dysfunction
The second cycle in the Twin Cycle Hypothesis centers on the pancreas. The fatty liver not only disrupts normal glucose production but also increases the liver’s export of triglycerides in the form of very-low-density lipoprotein (VLDL). When these fat-rich VLDL particles circulate in the bloodstream, they can deposit fat in various tissues, including the pancreas.

In the pancreas, the accumulation of fat within and around the insulin-producing beta cells has detrimental effects. Initially, the beta cells compensate by increasing insulin secretion to meet the body’s demands. However, chronic exposure to elevated levels of fatty acids—and in particular the toxic effects of saturated fatty acids like palmitic acid produced during de novo lipogenesis—leads to beta cell dysfunction. One of the early signs of this dysfunction is the loss of the first-phase insulin response, which is crucial for regulating blood glucose levels immediately after meals. As beta cell function deteriorates, their ability to secrete insulin in response to a glucose challenge is progressively impaired, and blood sugar levels begin to rise more dramatically.

Gradual Progression Over Years
The key insight of the Twin Cycle Hypothesis is that these processes occur slowly over many years. Initially, the body’s compensatory mechanisms—such as increased insulin secretion—mask the gradual rise in blood glucose levels. However, as liver fat continues to build up and more fat spills over to the pancreas, a tipping point is reached where beta cell function is sufficiently compromised, and overt type 2 diabetes develops. This long latency period explains why individuals may remain asymptomatic or have only mildly elevated blood glucose levels for an extended time before a sudden deterioration occurs.

Almost All People Can Reverse Insulin Resistance and Type 2 Diabetes
Importantly, the Twin Cycle Hypothesis also provides an explanation for why type 2 diabetes can be reversed, particularly in its early stages. Studies led by Dr. Roy Taylor have demonstrated that substantial weight loss—typically around 10–15% of body weight—can reduce fat in both the liver and pancreas. A decrease in liver fat restores hepatic insulin sensitivity, which rapidly normalizes fasting blood glucose levels. Over a slightly longer period, the reduction in pancreatic fat allows beta cells to recover their ability to secrete insulin normally. This reversal of the twin cycles confirms that type 2 diabetes is not an irreversible condition but rather a state of metabolic imbalance that, when corrected by sustained negative energy balance, can return to normal function.

Conclusion
In summary, the Twin Cycle Hypothesis breaks down the development of type 2 diabetes into two interconnected cycles: one in the liver and one in the pancreas. Chronic caloric excess, combined with inherent muscle insulin resistance, shunts surplus carbohydrates to the liver, leading to fat accumulation and hepatic insulin resistance. This sets up a vicious cycle of rising liver fat and insulin levels. The liver, in turn, exports fat to the pancreas, where it impairs beta cell function and diminishes insulin secretion. Over many years, these processes erode the body’s ability to regulate blood sugar, ultimately resulting in type 2 diabetes. The hypothesis not only elucidates the pathogenesis of the disease but also provides a framework for its reversal, emphasizing the importance of significant and sustained weight loss as a therapeutic strategy.