Also see:
The Streaming Organism
The Randle Cycle
Bisphenol A (BPA), Estrogen, and Diabetes
Insulin Inhibits Lipolysis
Aldosterone, Sodium Deficiency, and Insulin Resistance
Ray Peat, PhD on Brewer’s Yeast
Quotes by Ray Peat, PhD:
“Twenty-five years ago, some rabbits were made diabetic with a poison that killed their insulin-secreting pancreatic beta-cells, and when some of them recovered from the diabetes after being given supplemental DHEA, it was found that their beta-cells had regenerated. The more recent interest in stem cells has led several research groups to acknowledge that in animals the insulin-producing cells are able to regenerate.
It is now conceivable that there will be an effort to understand the factors that damage the beta-cells, and the factors that allow them to regenerate.”
“The thyroid gland is extremely adaptable and responsive, so it can go from zero to full activity in just two or three days. The adrenal glands are also very adaptive, except when they are continuously being destroyed by PUFA; they can fully regenerate in something like a couple of weeks. The pancreatic beta cells are also constantly turning over, regenerating, and “diabetes” is a condition in which they are continually being destroyed by PUFA.”
“Animals that have been made diabetic with relatively low doses of the poison streptozotocin can recover functional beta-cells spontaneously, and the rate of recovery is higher in pregnant animals (Hartman, et al., 1989). Pregnancy stabilizes blood sugar at a higher level, and progesterone favors the oxidation of glucose rather than fats.
A recent study suggests that recovery of the pancreas can be very fast. A little glucose was infused for 4 days into rats, keeping the blood glucose level normal, and the mass of beta-cells was found to have increased 2.5 times. Cell division wasn’t increased, so apparently the additional glucose was preventing the death of beta-cells, or stimulating the conversion of another type of cell to become insulin-secreting beta-cells (Jetton, et al., 2008).
That study is very important in relation to stem cells in general, because it either means that glandular cells are turning over (“streaming”) at a much higher rate than currently recognized in biology and medicine, or it means that (when blood sugar is adequate) stimulated cells are able to recruit neighboring cells to participate in their specialized function. Either way, it shows the great importance of environmental factors in regulating our anatomy and physiology.”
“I have known people who believed they had insulin deficiency, who recovered completely. The pancreas beta cells can regenerate quickly, polyunsaturated fats are continually damaging them.
The T3 component of the thyroid hormone makes muscles and other tissues oxidize sugar. Calcium, sodium, and aspirin are other things that increase the ability to use glucose.”
“Sugar can protect the beta-cells from the free fatty acids, apparently in the same ways that it protects the cells of blood vessels, restoring metabolic energy and preventing damage to the mitochondria. Glucose suppresses superoxide formation in beta-cells (Martens, et al., 2005) and apparently in other cells including brain cells. (Isaev, et al., 2008).
The beta-cell protecting effect of glucose is supported by bicarbonate and sodium. Sodium activates cells to produce carbon dioxide, allowing them to regulate calcium, preventing overstimulation and death. For a given amount of energy released, the oxidation of glucose produces more carbon dioxide and uses less oxygen than the oxidation of fatty acids.
The toxic excess of intracellular calcium that damages the insulin-secreting cells in the relative absence of carbon dioxide is analogous to the increased excitation of nerves and muscles that can be produced by hyperventilation.”
“Glucose and insulin which allows glucose to be used for energy production, while it lowers the formation of free fatty acids, promote the regeneration of the beta cells. Although several research groups have demonstrated the important role of glucose in regeneration of the pancreas, and many other groups have demonstrated the destructive effect of free fatty acids on the beta cells, the mainstream medical culture still claims that “sugar causes diabetes.”
Stem Cells. 2010 Sep;28(9):1630-8.
Pancreatic β-cell neogenesis by direct conversion from mature α-cells.
Chung CH, Hao E, Piran R, Keinan E, Levine F.
Because type 1 and type 2 diabetes are characterized by loss of β-cells, β-cell regeneration has garnered great interest as an approach to diabetes therapy. Here, we developed a new model of β-cell regeneration, combining pancreatic duct ligation (PDL) with elimination of pre-existing β-cells with alloxan. In this model, in which virtually all β-cells observed are neogenic, large numbers of β-cells were generated within 2 weeks. Strikingly, the neogenic β-cells arose primarily from α-cells. α-cell proliferation was prominent following PDL plus alloxan, providing a large pool of precursors, but we found that β-cells could form from α-cells by direct conversion with or without intervening cell division. Thus, classical asymmetric division was not a required feature of the process of α- to β-cell conversion. Intermediate cells coexpressing α-cell- and β-cell-specific markers appeared within the first week following PDL plus alloxan, declining gradually in number by 2 weeks as β-cells with a mature phenotype, as defined by lack of glucagon and expression of MafA, became predominant. In summary, these data revealed a novel function of α-cells as β-cell progenitors. The high efficiency and rapidity of this process make it attractive for performing the studies required to gain the mechanistic understanding of the process of α- to β-cell conversion that will be required for eventual clinical translation as a therapy for diabetes.
Trends Endocrinol Metab. 2011 Jan;22(1):34-43. Epub 2010 Nov 8.
β-cell regeneration: the pancreatic intrinsic faculty.
Desgraz R, Bonal C, Herrera PL.
Type I diabetes (T1D) patients rely on cumbersome chronic injections of insulin, making the development of alternate durable treatments a priority. The ability of the pancreas to generate new β-cells has been described in experimental diabetes models and, importantly, in infants with T1D. Here we discuss recent advances in identifying the origin of new β-cells after pancreatic injury, with and without inflammation, revealing a surprising degree of cell plasticity in the mature pancreas. In particular, the inducible selective near-total destruction of β-cells in healthy adult mice uncovers the intrinsic capacity of differentiated pancreatic cells to spontaneously reprogram to produce insulin. This opens new therapeutic possibilities because it implies that β-cells can differentiate endogenously, in depleted adults, from heterologous origins.
Bioessays. 2010 Oct;32(10):881-4. doi: 10.1002/bies.201000074. Epub 2010 Aug 27.
A new paradigm in cell therapy for diabetes: turning pancreatic α-cells into β-cells.
Sangan CB, Tosh D.
Cell therapy means treating diseases with the body’s own cells. One of the cell types most in demand for therapeutic purposes is the pancreatic β-cell. This is because diabetes is one of the major healthcare problems in the world. Diabetes can be treated by islet transplantation but the major limitation is the shortage of organ donors. To overcome the shortfall in donors, alternative sources of pancreatic β-cells must be found. Potential sources include embryonic or adult stem cells or, from existing β-cells. There is now a startling new addition to this list of therapies: the pancreatic α-cell. Thorel and colleagues recently showed that under circumstances of extreme pancreatic β-cell loss, α-cells may serve to replenish the insulin-producing compartment. This conversion of α-cells to β-cells represents an example of transdifferentiation. Understanding the molecular basis for transdifferentiation may help to enhance the generation of β-cells for the treatment of diabetes.
Nature. 2010 Apr 22;464(7292):1149-54. Epub 2010 Apr 4.
Conversion of adult pancreatic alpha-cells to beta-cells after extreme beta-cell loss.
Thorel F, Népote V, Avril I, Kohno K, Desgraz R, Chera S, Herrera PL.
Pancreatic insulin-producing beta-cells have a long lifespan, such that in healthy conditions they replicate little during a lifetime. Nevertheless, they show increased self-duplication after increased metabolic demand or after injury (that is, beta-cell loss). It is not known whether adult mammals can differentiate (regenerate) new beta-cells after extreme, total beta-cell loss, as in diabetes. This would indicate differentiation from precursors or another heterologous (non-beta-cell) source. Here we show beta-cell regeneration in a transgenic model of diphtheria-toxin-induced acute selective near-total beta-cell ablation. If given insulin, the mice survived and showed beta-cell mass augmentation with time. Lineage-tracing to label the glucagon-producing alpha-cells before beta-cell ablation tracked large fractions of regenerated beta-cells as deriving from alpha-cells, revealing a previously disregarded degree of pancreatic cell plasticity. Such inter-endocrine spontaneous adult cell conversion could be harnessed towards methods of producing beta-cells for diabetes therapies, either in differentiation settings in vitro or in induced regeneration.
Diabetes. 2012 Mar;61(3):632-41. Epub 2012 Feb 14.
Free fatty acids block glucose-induced β-cell proliferation in mice by inducing cell cycle inhibitors p16 and p18.
Pascoe J, Hollern D, Stamateris R, Abbasi M, Romano LC, Zou B, O’Donnell CP, Garcia-Ocana A, Alonso LC.
Pancreatic β-cell proliferation is infrequent in adult humans and is not increased in type 2 diabetes despite obesity and insulin resistance, suggesting the existence of inhibitory factors. Free fatty acids (FFAs) may influence proliferation. In order to test whether FFAs restrict β-cell proliferation in vivo, mice were intravenously infused with saline, Liposyn II, glucose, or both, continuously for 4 days. Lipid infusion did not alter basal β-cell proliferation, but blocked glucose-stimulated proliferation, without inducing excess β-cell death. In vitro exposure to FFAs inhibited proliferation in both primary mouse β-cells and in rat insulinoma (INS-1) cells, indicating a direct effect on β-cells. Two of the fatty acids present in Liposyn II, linoleic acid and palmitic acid, both reduced proliferation. FFAs did not interfere with cyclin D2 induction or nuclear localization by glucose, but increased expression of inhibitor of cyclin dependent kinase 4 (INK4) family cell cycle inhibitors p16 and p18. Knockdown of either p16 or p18 rescued the antiproliferative effect of FFAs. These data provide evidence for a novel antiproliferative form of β-cell glucolipotoxicity: FFAs restrain glucose-stimulated β-cell proliferation in vivo and in vitro through cell cycle inhibitors p16 and p18. If FFAs reduce proliferation induced by obesity and insulin resistance, targeting this pathway may lead to new treatment approaches to prevent diabetes.
Diabetes March 2012 vol. 61 no. 3 560-561
Does Inhibition of β-Cell Proliferation by Free Fatty Acid in Mice Explain the Progressive Failure of Insulin Secretion in Type 2 Diabetes?
Guenther Boden
Eur J Clin Invest. 2002 Jun;32 Suppl 3:14-23.
Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction.
Boden G, Shulman GI.
Plasma free fatty acids (FFA) play important physiological roles in skeletal muscle, heart, liver and pancreas. However, chronically elevated plasma FFA appear to have pathophysiological consequences. Elevated FFA concentrations are linked with the onset of peripheral and hepatic insulin resistance and, while the precise action in the liver remains unclear, a model to explain the role of raised FFA in the development of skeletal muscle insulin resistance has recently been put forward. Over 30 years ago, Randle proposed that FFA compete with glucose as the major energy substrate in cardiac muscle, leading to decreased glucose oxidation when FFA are elevated. Recent data indicate that high plasma FFA also have a significant role in contributing to insulin resistance. Elevated FFA and intracellular lipid appear to inhibit insulin signalling, leading to a reduction in insulin-stimulated muscle glucose transport that may be mediated by a decrease in GLUT-4 translocation. The resulting suppression of muscle glucose transport leads to reduced muscle glycogen synthesis and glycolysis. In the liver, elevated FFA may contribute to hyperglycaemia by antagonizing the effects of insulin on endogenous glucose production. FFA also affect insulin secretion, although the nature of this relationship remains a subject for debate. Finally, evidence is discussed that FFA represent a crucial link between insulin resistance and beta-cell dysfunction and, as such, a reduction in elevated plasma FFA should be an important therapeutic target in obesity and type 2 diabetes.
PUFA destroy beta cells:
“The antimetabolic and toxic effects of the polyunsaturated fatty acids can account for the “insulin resistance” that characterizes type-2 diabetes, but similar actions in the pancreatic beta-cells can impair or kill those cells, creating a deficiency of insulin, resembling type-1 diabetes.” -Ray Peat, PhD
Endocrine. 2011 Apr;39(2):128-38. Epub 2010 Dec 15.
Long-term exposure of INS-1 rat insulinoma cells to linoleic acid and glucose in vitro affects cell viability and function through mitochondrial-mediated pathways.
Tuo Y, Wang D, Li S, Chen C.
Obesity with excessive levels of circulating free fatty acids (FFAs) is tightly linked to the incidence of type 2 diabetes. Insulin resistance of peripheral tissues and pancreatic β-cell dysfunction are two major pathological changes in diabetes and both are facilitated by excessive levels of FFAs and/or glucose. To gain insight into the mitochondrial-mediated mechanisms by which long-term exposure of INS-1 cells to excess FFAs causes β-cell dysfunction, the effects of the unsaturated FFA linoleic acid (C 18:2, n-6) on rat insulinoma INS-1 β cells was investigated. INS-1 cells were incubated with 0, 50, 250 or 500 μM linoleic acid/0.5% (w/v) BSA for 48 h under culture conditions of normal (11.1 mM) or high (25 mM) glucose in serum-free RPMI-1640 medium. Cell viability, apoptosis, glucose-stimulated insulin secretion, Bcl-2, and Bax gene expression levels, mitochondrial membrane potential and cytochrome c release were examined. Linoleic acid 500 μM significantly suppressed cell viability and induced apoptosis when administered in 11.1 and 25 mM glucose culture medium. Compared with control, linoleic acid 500 μM significantly increased Bax expression in 25 mM glucose culture medium but not in 11.1 mM glucose culture medium. Linoleic acid also dose-dependently reduced mitochondrial membrane potential (ΔΨm) and significantly promoted cytochrome c release from mitochondria in both 11.1 mM glucose and 25 mM glucose culture medium, further reducing glucose-stimulated insulin secretion, which is dependent on normal mitochondrial function. With the increase in glucose levels in culture medium, INS-1 β-cell insulin secretion function was deteriorated further. The results of this study indicate that chronic exposure to linoleic acid-induced β-cell dysfunction and apoptosis, which involved a mitochondrial-mediated signal pathway, and increased glucose levels enhanced linoleic acid-induced β-cell dysfunction.
J Clin Endocrinol Metab. 2013 May;98(5):2062-9. doi: 10.1210/jc.2012-3492. Epub 2013 Mar 22.
β-Cell Lipotoxicity After an Overnight Intravenous Lipid Challenge and Free Fatty Acid Elevation in African American Versus American White Overweight/Obese Adolescents.
Hughan KS, Bonadonna RC, Lee S, Michaliszyn SF, Arslanian SA.
Objective: Overweight/obese (OW/OB) African American (AA) adolescents have a more diabetogenic insulin secretion/sensitivity pattern compared with their American white (AW) peers. The present study investigated β-cell lipotoxicity to test whether increased free fatty acid (FFA) levels result in greater β-cell dysfunction in AA vs AW OW/OB adolescents. Research Design and Methods: Glucose-stimulated insulin secretion was modeled, from glucose and C-peptide concentrations during a 2-hour hyperglycemic (225 mg/dL) clamp in 22 AA and 24 AW OW/OB adolescents, on 2 occasions after a 12-hour overnight infusion of either normal saline or intralipid (IL) in a random sequence. β-Cell function relative to insulin sensitivity, the disposition index (DI), was examined during normal saline and IL conditions. Substrate oxidation was evaluated with indirect calorimetry and body composition and abdominal adiposity with dual-energy X-ray absorptiometry and magnetic resonance imaging at L4-L5, respectively. Results: Age, sex, body mass index, total and sc adiposity were similar between racial groups, but visceral adiposity was significantly lower in AAs. During IL infusion, FFAs and fat oxidation increased and insulin sensitivity decreased similarly in AAs and AWs. β-Cell glucose sensitivity of first- and second-phase insulin secretion did not change significantly during IL infusion in either group, but DI in each phase decreased significantly and similarly in AAs and AWs. Conclusions: Overweight/obese AA and AW adolescents respond to an overnight fat infusion with significant declines in insulin sensitivity, DI, and β-cell function relative to insulin sensitivity, suggestive of β-cell lipotoxicity. However, contrary to our hypothesis, there does not seem to be a race differential in β-cell lipotoxicity. Longer durations of FFA elevation may unravel such race-related contrasts.
