Where Are All The Beta Cells?

What Exactly Is Diabetes?

In 2023, the International Diabetes Federation announced that 529 million people worldwide had type-2 diabetes and that the disease is responsible for 4.6 million deaths each year, or one death every five seconds. It affects ~12% of US adults, and >25% of those over the age of 65. Diabetes is no longer restricted to the Western world, and the greatest increase in disease incidence in the next few decades is expected to be in China and India. It is predicted to affect 1.3 billion people by 2050. These figures serve to emphasize there is currently a fast-growing diabetes pandemic. This is a major health-care problem because diabetes increases the risk of heart disease, stroke and microvascular complications such as blindness, renal failure, and peripheral neuropathy. Consequently, it places a severe economic burden on governments and individuals: the cost of diabetes and its complications amounts to $612 million per day in the USA alone.

As we covered in a previous newsletter, the COVID pandemic will also likely lead to a wave of new diabetes cases in the near-future.

Diabetes is characterized by high blood glucose levels as a result of insufficient insulin for the body's needs. It is a heterogeneous disorder with multiple etiologies. Type-1 diabetes (T1DM) is an autoimmune disease that results in beta-cell destruction. It usually presents in childhood, accounts for 5-10% of all diabetes, is associated with the presence of islet-cell antibodies, and patients require lifelong insulin. Type-2 diabetes (T2DM), the most common form of the disease, is influenced by lifestyle factors, such as age, pregnancy and obesity, but has a strong genetic component. Multiple genes are thought to be involved, each producing a small effect on T2DM risk. 96% of all diabetes cases are type 2. An increasing number of rare monogenic forms of diabetes have also been identified that result from mutations in a single gene.

Meet The Beta Cell

Pancreatic beta cells play a critical role in maintaining glucose homeostasis by serving as the primary source of insulin. These cells are responsible for the synthesis, storage, and release of insulin, which is tightly regulated in response to changes in the body’s metabolic status. It is perhaps one of the most important cells in the human body. Beta cells have an average diameter of 10 μm, contain about 20 pg insulin per cell, and are the predominant cell type in the pancreatic islets (50–80% of all islet endocrine cells).

The physiological regulation of insulin secretion from the pancreatic beta cells is now fairly well understood. It involves exquisite sensing of blood glucose, increased energy production by the beta cells in response, and ultimately influx of calcium into the cells resulting in release of insulin. Making insulin is very hard work for these cells indeed, and this process is highly regulated.

Where Do Beta Cells Come From?

The formation of beta cells in the pancreas has been studied extensively thanks to murine models. The definitive endoderm, from which the pancreas arises, begins as a flat sheet of cells that is specified during gastrulation. Genes required for definitive endoderm formation include Wnt/β-catenin, Nodal, GATA4/6, FoxA2, Sox17, and Mix. Pancreatic specification becomes evident around embryonic day 8.5 (E8.5) with the expression of pancreatic duodenal homeobox 1 (Pdx1) in two ventral domains. Insulin expressing beta cells are the first endocrine cells to appear in the human pancreas and we talked about Pdx1 in a previous newsletter about the Hagfish. Pdx1 is a very ancient, very conserved, and very important gene.

Reports on the precise appearance of the different lineages vary, but by E13.5–E14.5 all five hormone-expressing endocrine lineages (α, β, δ, ε, and PP) are detectable. Emergence of amylase-expressing acinar cells commences around this time as well.

What Happens To Beta Cells In Diabetes?

A hallmark of type 2 diabetes (T2DM) is the reduction in functional β-cell mass, which is considered at least in part to result from an imbalance of β-cell renewal and apoptosis (cell death), with the latter being accelerated during metabolic stress. Functional β-cell failure is detectable very early - even before diabetes diagnosis and shows a relentless progression despite pharmacotherapy. Although insulin resistance is part of the story of the development of T2DM, in large clinical trials, treatment of insulin resistance shows success with respect to outcomes but does not address the continued deterioration in β-cell function.

Several mechanisms underlying a reduction in functional β-cell mass have been proposed. Analysis of pancreas specimens from cadaveric human donors show an approximately 50% reduction in β-cell mass in humans who had been diagnosed with T2DM as compared to adequately matched controls. How exactly does this happen has been the subject of intense study.

In multiple models of T2DM and metabolic stressors to β-cells, a loss of β-cells results from dedifferentiation of mature β-cells into a multipotent state, from which some cells likely differentiate towards an α-cell phenotype. This suggests that oxidative and mitochondrial stress results in increased oxidative damage to β-cells and may be a principal driver of β-cell de-differentiation.

As it turns out there may be some states that inherently predispose and prime the pancreas beta cells to fail. Over the last 5-6 years, over 40 genes have been identified that confer an increased risk of developing T2DM. The most important diabetes susceptibility gene identified to date is TCF7L2, which increases diabetes risk 1.7-fold. In addition, there are likely other factors at work as well, since β-cell mass appears to be determined during the first few years of life and well before most individuals are diagnosed with T2DM. Individuals endowed with a relatively low β-cell mass at the start of their lives may lack sufficient reserve to adapt to metabolic demands such as obesity-related insulin resistance (context-dependent β-cell failure) and be at increased risk of developing T2DM.

The actual stressors can vary, but usually center around both the high glucose and high lipid toxic metabolic states. In a nutshell, continuous and hyper-physiologic glucose and/or lipid levels in the blood can directly damage beta cells through intermediary production of free radicals after continuous and prolonged overstimulation of the beta cells. In an interesting turn of events, the body's own microbiome may produce a protective anti-oxidant chemical, trimethylamine (metabolized in the liver to trimethylamine N-oxide (TMAO)) after chronic exposure to a diet that raises lipid levels. This compound actually protects the beta cell against free radical damage as was shown in this elegant study in 2021.

Other toxins present in the environment are also particularly toxic to the beta cell. These include dioxin, organophosphate pesticides, persistent organic pollutants (POP), and heavy metals. This paper summarizes the evidence well.

What is becoming very clear though is that, over time, beta cells become damaged, exhausted, and dedifferentiated until the clinical state of diabetes becomes evident.

Can Anything Be Done To Stop This Progression To Diabetes?

There is mounting evidence that early and aggressive use of insulin can "rest" beta cells and allow them to potentially recover. The author of one review suggests that people newly diagnosed with T2DM and A1C?>9% should receive early transient intensive insulin therapy to achieve normoglycemia within weeks of diagnosis. Newer evidence suggests a similar benefit with the use of GLP-1 RA drugs like liraglutide, as was shown in the GRADE trial published in the New England Journal of Medicine in 2022.

Intriguing evidence suggests that bariatric surgery also can derail the development of diabetes long before significant weight loss occurs. The mechanisms involved have not yet been elucidated but proposed explanations include increased release of the incretin hormone GLP-1, an altered gut microbiome, and caloric restriction. Caloric restriction by itself (< 600 kcal/day) results in reversal of diabetes especially in patients who have had it for only a few years. Obviously weight loss plays a very significant role.

Finally, in one of our previous newsletters, you learned that exercise can increase beta cell mass significantly.

What About Just Replacing Beta Cells With New Ones?

As we have seen, over the last 15 years much knowledge has been gained as to what cellular switches need to be thrown to grow a beta cell.

There is considerable hope that the application of this knowledge will optimize efforts to generate β cells from precursor or stem cells ex vivo, thereby providing a potentially limitless source of β cells for transplantation into patients with diabetes.

Conclusion

The biology of pancreatic beta cells is intricate and complex. Much has been learned about how they work, how they form and how they fail. Many questions remain. For example, do variations in certain diabetes susceptibility genes increase the propensity of β-cell dedifferentiation? Are there a subset population of β cells that are more likely to suffer cell death? More importantly, are there clinical biomarkers that will identify pre-diabetics who will benefit from pre-emptive therapy to prevent β-cell de-differentiation? The future holds great promise indeed.

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