Diabetes-lucky dip Flashcards
What are the primary goals of treatment for Type 1 diabetes (T1D), and what are some future considerations for achieving these goals?
The primary goals are to preserve or replace endogenous insulin production, reduce the disability associated with insulin deficiency, and improve quality of life. Future considerations include ensuring long-term sustainability and equitable access to these treatments.
What are two key advantages and two disadvantages of islet transplantation for treating T1D?
Advantages of islet transplantation: (1) It can achieve insulin independence for some individuals. (2) It significantly improves health-related quality of life, particularly for those experiencing severe hypoglycemia.
Disadvantages: (1) It requires lifelong immunosuppression, which carries risks. (2) The availability of donor islets is limited.
What is the significance of using human stomach samples to generate islet-like organoids (GINs) for T1D treatment?
Stomach tissues, specifically hGSCs, have shown a greater propensity for adopting a β-cell fate compared to intestinal tissues. This makes them a promising source for generating GINs for potential T1D treatment.
Describe the process by which GINs are generated from human gastric stem cells (hGSCs).
hGSCs are first engineered to express NGN3 transiently, followed by stable PDX1 and MAFA expression. These engineered cells are then aggregated into spherical organoids and cultured in a chemically defined, serum-free medium that promotes differentiation into GINs.
What evidence suggests that GINs possess functional characteristics similar to pancreatic islets?
GINs exhibit
- glucose-stimulated insulin secretion (GSIS),
- secrete human insulin in response to glucose and GLP-1 analogs, and
- contain a significant proportion of C-peptide expressing (CPPT+) cells,
similar to pancreatic islets
How did researchers investigate the developmental trajectory of GINs, and what key cell type was identified as a precursor to β-like cells?
Researchers used single-cell RNA sequencing (scRNA-seq) to track the differentiation of hGSCs into GINs. They identified Galanin+ (GAL+) cells as a precursor to β-like cells in GINs.
What are some limitations of using GINs as a potential treatment for T1D, and what future research is needed to address these limitations?
(1) GINs currently lack a significant number of α- and δ-like cells, which are crucial for fine-tuning glucose responsiveness.
(2) The long-term functionality and safety of transplanted GINs require further evaluation.
(3) There are species-specific differences in the response to inducing factors, requiring further research.
What is the rationale for targeting the glucagon receptor (GCGR) with an antagonist like volagidemab in T1D treatment?
In T1D, hyperglucagonemia contributes to hyperglycemia. Blocking the GCGR with an antagonist like volagidemab aims to reduce glucagon action and improve glycemic control.
What were the primary and secondary endpoints in the Phase 2 trial of volagidemab for T1D, and what were the key findings regarding these endpoints?
Primary endpoint: The primary endpoint was the change in daily insulin use at week 12. Volagidemab showed a reduction in insulin use, though it did not meet the prespecified significance level. Secondary endpoints: Included changes in HbA1c, average daily blood glucose, time in target range, hypoglycemic events, and volagidemab concentrations. Notably, volagidemab reduced HbA1c without increasing hypoglycemia.
Describe the potential adverse effects of volagidemab observed in the Phase 2 trial, and explain why further investigation is needed
Potential adverse effects: Volagidemab was associated with increases in serum transaminases (ALT and AST), LDL-cholesterol, and blood pressure. These findings require further investigation in larger, longer-term trials to assess their clinical significance and long-term impact.
What are GINS organoids?
GINS organoids are a type of lab-grown mini-organ that secretes insulin in response to glucose. They are derived from human gastric stem cells (hGSCs) taken from stomach biopsies. These hGSCs are then reprogrammed in a multi-step process into insulin-producing cells by activating specific genes such as NGN3, PDX1, and MAFA, as well as by culturing them in a specific serum-free medium that includes nicotinamide and a ROCK inhibitor.
What cell types do GINS organoids contain?
Single-cell RNA sequencing (scRNA-seq) has shown that GINS organoids contain four main endocrine cell types that are similar to those found in pancreatic islets: β-like cells, α-like cells, δ-like cells, and ε-like cells. However, the majority of cells in GINS organoids are β-like cells that express insulin.
How do GINS organoids function?
GINS organoids secrete insulin in response to glucose and a GLP-1 analogue, just like β-cells found in the pancreas. This glucose-stimulated insulin secretion (GSIS) has been demonstrated both in static incubation and in dynamic perifusion assays. Notably, antral GINS organoids exhibit robust GSIS in vitro, similar to corpus-derived organoids
How are GINS organoids different from islet β-cells?
Although GINS cells closely resemble islet β-cells in terms of their function and molecular identity, there are some differences. For example, GINS cells have lower ribonucleoprotein biogenesis activity compared to islet β-cells, suggesting a degree of functional immaturity. Additionally, while transplanted GINS cells express mature β-cell markers, their electron-dense granules are not fully condensed
Can GINS organoids be used to treat diabetes?
Preliminary studies in mice have shown promising results. When transplanted into diabetic mice, GINS cells successfully reversed diabetes, with blood glucose levels significantly decreasing and glucose tolerance improving. Furthermore, the transplanted cells survived for at least six months, indicating long-term functionality.
