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Is insulin resistance a cause or a consequence of aging?

Image credit: Park et al, 2015 https://europepmc.org/article/med/26219845

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Shubhankar Kulkarni
Shubhankar Kulkarni Aug 05, 2020
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Insulin resistance was previously considered a cause of type 2 diabetes. Recent studies have suggested other mechanisms that precede insulin resistance and that they have a role in establishing insulin resistance. If we consider type 2 diabetes as an age-related disorder, we might consider insulin resistance as a consequence of aging.

We know for certain that insulin resistance and longevity are associated. Metabolic syndrome consists of metabolic defects associated with increased risks of reduced longevity and other age-related disorders. The metabolic syndrome of aging was originally called insulin resistance syndrome, pointing to insulin resistance as the key factor. In older persons, age-related rise of visceral adiposity and accumulation of senescent cells with inflammatory phenotype results in high blood levels of proinflammatory cytokines that probably interfere with insulin signaling. Insulin resistance contributes to increased cardiovascular morbidity in part through impairments in lipid uptake and storage of circulating lipids leading to increased plasma levels of very-low-density lipoprotein (proatherogenic apoB-containing/triglyceride-rich lipoproteins). Due to its high prevalence and strong association with many adverse outcomes, insulin resistance is often considered to have a causal role in many adverse aging phenotypes and age-related conditions, and counteracting insulin resistance could be an effective “anti-aging” intervention. This is suported by the use of metformin (an anti-diabetic drug) to combat other aging-related disorders and increase longevity. This view is, however, in contrast with the widely accepted notion that a downregulation (by genetic modulation) of the insulin signaling pathway in invertebrates is associated with exceptional longevity. Furthermore, it is suggested that in mammals, enhanced insulin sensitivity is neither a necessary nor a sufficient step towards increased longevity. Therefore, to answer whether insulin resistance is a cause or a consequence of aging, we need answers to:

  1. Is type 2 diabetes an age-related disorder?
  2. What molecular pathways connect insulin resistance and aging?

The answer to whether insulin resistance is a cause or consequence of aging may help in treating either with the medications used to treat the other.

[1]Watve M. Doves, diplomats and diabetes: a Darwinian interpretation of type 2 diabetes and related disorders. New York: Springer, 2013

[2]Corkey B. Banting Lecture 2011: Hyperinsulinemia: Cause or Consequence? Diabetes. 2011;61:4–13. doi: 10.2337/db11-1483.

[3]Ford ES, Giles WH, Dietz WH. Prevalence of the Metabolic Syndrome Among US Adults. JAMA [Internet]. 2002 Jan 16;287(3):356. Available from: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.287.3.356

[4]Sepe A, Tchkonia T, Thomou T, Zamboni M, Kirkland JL. Aging and Regional Differences in Fat Cell Progenitors – A Mini-Review. Gerontology [Internet]. 2011;57(1):66–75. Available from: https://www.karger.com/Article/FullText/279755

[5]Barzilai N, Ferrucci L. Insulin Resistance and Aging: A Cause or a Protective Response? Journals Gerontol Ser A Biol Sci Med Sci [Internet]. 2012 Dec 1;67(12):1329–31. Available from: https://academic.oup.com/biomedgerontology/article-lookup/doi/10.1093/gerona/gls145

[6]Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP, Schernthaner G, et al. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes, Obes Metab [Internet]. 2014 Nov;16(11):1165–73. Available from: http://doi.wiley.com/10.1111/dom.12354

[7]Tatar M, Bartke A, Antebi A. The Endocrine Regulation of Aging by Insulin-like Signals. Science (80- ) [Internet]. 2003 Feb 28;299(5611):1346–51. Available from: https://www.sciencemag.org/lookup/doi/10.1126/science.1081447

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Shireesh Apte
Shireesh Apte18 hours ago
The literature suggests that Insulin resistance is a protective mechanism against carcinogenesis. This is a view that has not yet been fathomed by the scientific community. I have uploaded part of my manuscript below:
The scientific establishment; in recent years; and in the face of persuasive mounting evidence; is actively considering the proposition that type 2 diabetes (T2D) – the most common end stage in the development of metabolic syndrome - may be the manifestation of a protective response (1,2) against the metabolic reprogramming of, or the oxidative damage to cells (3-6). Prevailing dogma for the treatment of T2D entails reducing hyperglycemia by promoting the intracellular uptake of glucose and restoring insulin sensitivity (7). Insulin sensitizers such as thiazolidinediones and insulin secretagogues such as sulfonylureas and incretin mimetics (including GLP-1 agonists and DPP-4 inhibitors) form the mainstay of treatment. However, if nutritional excess (8), oxidative stress (9-12), mitochondrial dysfunction (13-22), hyperinsulinemia (23-27) and/or metabolic reprogramming (28,29) are sufficient (30) in and of themselves to bidirectionally (31) induce (viz., be both the cause (32) and consequence of (33)) cell size (34) and cell type-dependent cellular resistance to insulin, then the current paradigm of circumventing such resistance is fallacious and self-defeating, the ostensible success in reducing hyperglycemia and the abatement of secondary cardiovascular symptoms by driving glucose into cells is pyrrhic and the inconspicuous propensity to cause carcinogenesis is obliviously tragic. Instead, what is required are caloric restriction, diet (35) and lifestyle changes (36), which can significantly reduce glucose intolerance, or foods and drugs that reduce hyperglycemia by insulin independent mechanisms of action (37); such as by increasing glucose excretion, not glucose utilization.
Sodium glucose cotransporter 2 (SGLT2) inhibitors such as emplagliflozin (Jardiance®) and canagliflozin (Invokana®) - among others - accomplish precisely this; they reduce the reabsorption of glucose by the proximal tubule, thus increasing glycosuria (38,39). Auxillary benefits include caloric and volumetric loss thereby concomitantly decreasing body weight and blood pressure respectively (40). Unlike sensitizers and secretagogues, which do not reduce insulin demand, SGLT2 inhibitors improve glycemic control independent of insulin secretion resulting in β-cell sparing effects (41). Consistent with this revised model of T2D providing protection against excessive glucose utilization to drive Warburgian aerobic glycolysis, SGLT2 inhibitors exhibit anti-carcinogenic effects in animal models of pancreatic, hepatocellular (42,43) and prostate adenocarcinomas (44). Even though overexpression of glucose transporters (GLUTs) may satisfy the ATP-free import of glucose into cancer cells, it has been proposed that ATP-dependent SGLTs are expressed on cancer cells (45) to sustain glucose uptake against an uphill glucose gradient, that in turn arises due to fast/disordered cellular growth in a hypoxic environment (46).
Since by definition, a “diabetic patient” has been so diagnosed and is likely to be on medication, epidemeological data that suggest that T2D can predispose to the development of cancer (47) could be interpreted to mean that the conventional treatment ofT2D with insulin sensitizers (48) and secretagogues (49) can predispose patients to the development of cancer (50-52), within the context of forcing as-yet non-transformed recalcitrant cells - which have invoked protective mechanisms to prevent glucose ingress - to utilize more glucose. (The treatment of) Diabetes is a risk-factor for cancer because the existing paradigm for treating diabetes makes it so (53). The profound significance of this proposed new model cannot be overestimated since it presents a disconcerting possibility that the current model for treating T2D exacerbates carcinogenic propensity (54), going so far as to engineer the overexpression of GLUT (55)and to increase intracellular oxidative stress (56). Unsurprisingly, as a consequence of this misguided treatment strategy, the medical community has resigned to designating the development of cancer as one of the complications or comorbidities of T2D (57).
Signaling pathway molecules that intersect with SGLT2 in beneficial ways; such as peroxisome proliferator-activated receptor δ (PPAR-δ) agonists cause inhibition of SGLT2 function by increasing adiponectin levels (58). Adeponectin is also increased by SGLT2 inhibitors (59)and PPAR-ɣ agonists (60). Furthermore, adeponectin is the downstream effector of the pleiotropic metabolic hormone, Fibroblast growth factor 21 (FGF21) (61). Hypoadeponectinemia is associated with an increase in insulin resistance (62, 63). SGLT2 inhibitors suppress triple negative breast cancer cell growth by reducing the phosphorylation of PI3K/AkT and Erk (64). The PPAR[ɣ and δ] – FGF21- Adeponectin – SGLT2 axis; and the food ingredients that activate it; may thus modulate glycosuria and alleviate the secondary symptoms of T2D without driving carcinogenesis.
FGF21 agonists or analogs exert their metabolic action by increasing adiponectin levels and by stimulating brown fat thermogenesis in adipose tissue (65). Activating FGF21 decreases renal glucose reabsorption by the PPARδ mediated inhibition of SGLT2 (66)and decreases intestinal glucose uptake by downregulating intestinal SGLT1 expresssion (67). FGF21 is necessary for the reduction in adiposity mediated by SGLT2 inhibitors (68).
Considering that identical blood glucose values can be associated with dysmetabolic states and vice versa, blood glucose concentration is a poor marker of general metabolism or of glucose fluxes (69). The cell, tissue or organ specific difference in intra and extracellular glucose, or the blood insulin level may more accurately describe dysmetabolic or dyslipidemic states. This author could not find any literature that measured intracellular glucose concentrations during hyper, hypo or euglycemic conditions, although methodology to measure glucose in a single cell exists (70). Such information would be extremely useful to disentangle and extricate the often conflicting and overlapping effects of myriad signaling pathways on the cause or consequences of T2D. Research to decrease hyperinsulinemia – which often predates the diagnosis of T2D (71) - includes identification of chaperone proteins responsible for the correct folding of the insulin precursor – proinsulin, in the pancreas (72). Bariatric surgery on obese patients has long been known to reverse insulin resistance (73) and seems to provide long term remission from T2D (74, 75). Proposed mechanisms range from gut hormonal or microbiome changes (76) to the attenuation of an as-yet-undiscovered anti-incretin factor from the surgically excluded forgut (77). Fractyl laboratories (78), MA, has ongoing clinical trials on its hydrothermal duodenal mucosal resurfacing outpatient procedure to restore insulin sensitivity.
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