New opportunities: harnessing induced pluripotency for discovery in diabetes and metabolism

Abstract

The landmark discovery of induced pluripotent stem cells (iPSCs) by Shinya Yamanaka has transformed regenerative biology. Previously, insights into the pathogenesis of chronic human diseases have been hindered by the inaccessibility of patient samples. However, scientists are now able to convert patient fibroblasts into iPSCs and differentiate them into disease-relevant cell types. This ability opens new avenues for investigating disease pathogenesis and designing novel treatments. In this review, we highlight the uses of human iPSCs to uncover the underlying causes and pathological consequences of diabetes and metabolic syndromes, multifactorial diseases whose etiologies have been difficult to unravel using traditional methodologies.

Figure 1. Types of diabetes and metabolic syndromes

The various types of diabetes and metabolic syndromes that can be modeled using induced pluripotent stem cells (iPSCs) include monogenic forms of diabetes, Type 1 diabetes (T1D) and Type 2 diabetes (T2D). T1D occurs as a result of immune attack by immune cells such as macrophages and T cells whereas T2D occurs as a result of insulin resistance in the pancreas, muscle, fat and liver. Square represents male subjects whereas circle represents female subjects. Filled symbols denote subjects with diabetes.

Figure 2. Schematic of derivation of hiPSCs from patient somatic cells

Types of human somatic cells which are relatively more accessible for reprogramming include keratinocytes, dermal fibroblasts, adipocytes and peripheral blood cells. Current reprogramming methods include the use of retroviruses, lentiviruses, plasmids, adenoviruses, Sendai viruses, transposons, protein, modified RNA and miRNA.

Figure 3. Differentiation of diabetic hiPSCs into various cell types forin vitrodisease modeling

Each type/source of diabetic hiPSCs can be differentiated into relevant cell types of interest for investigating disease mechanisms. Cell types of interest include pancreatic cells, cells involved in diabetic complications and cells involved in insulin resistance.