Type 2 Diabetes Pathogenesis

Does Insulin Resistance Cause hyperinsulinemia?

Type 2 diabetes is a major metabolic disease characterized by hyperglycemia and insulin resistance, affecting over 390 million people around the globe (1). The traditional hypothesis for its pathogenesis is that obesity leads to insulin resistance and hyperglycemia, resulting in compensatory hyperinsulinemia and, eventually, the diabetic phenotype (2).

However, this hypothesis does not explain a host of curious phenomena, such as why some obese individuals have hyperinsulinemia without insulin resistance or hyperglycemia. Additionally, experimentally induced hyperinsulinemia can cause insulin resistance; so, the question is, Which comes first in the development of diabetes: insulin resistance or hyperinsulinemia (3)?

Insulin Resistance

Being the older notion of the two, the “insulin resistance first” hypothesis is supported by historical and experimental evidence. Genetic studies over the years have linked mutations in the insulin pathway to a higher risk of diabetes (see insulin pathway poster for the major players). Experimental data support this notion as well; various genetic mouse models with induced insulin resistance develop diabetes (3).

Hyperinsulinemia

Although the “insulin resistance first” hypothesis is supported by years of evidence, it is not impervious to criticism and skepticism (4). First, research on juveniles has shown that hyperinsulinemia can precede obesity and insulin resistance (5). Second, disrupting insulin feedback inhibition mechanisms in beta cells (6) or increasing insulin gene dosage (7) can drive insulin resistance and obesity in mouse models.

Therefore, both hyperinsulinemia and insulin resistance have experimental backing as possible routes toward [CE1] diabetes, and, tragically, each can influence the other in a positive feedback loop. The key to determining which has more human relevance is developing technology of suitable sensitivity to track minute changes in insulin, blood glucose, and peripheral insulin sensitivity for longitudinal human investigations. A clearer understanding of the timeline of diabetes development may lead to novel therapeutic interventions and earlier detection methods.

Related Antibodies

References:

1. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.
2. Pathogenesis of NIDDM. A balanced overview.
3. Insulin action and resistance in obesity and type 2 diabetes.
4. Hyperinsulinemia: a Cause of Obesity?
5. Early changes in postprandial insulin secretion, not in insulin sensitivity, characterize juvenile obesity.
6. Hyperinsulinemia precedes insulin resistance in mice lacking pancreatic beta-cell leptin signaling.
7. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production.