July 3, 2018, selected research digest

Reading Time: 4 minutes

Type 2 Diabetes: The Pathologic Basis of Reversible β-Cell Dysfunction. As disease progresses in a type 2 diabetic, insulin-secreting cells can dedifferentiate and stop secreting insulin. When weight loss occurs, these cells can re-differentiate and begin secreting insulin again. Early insulin dysfunction (<10 years) is reversible in T2DM. Questions: The authors claim 10 years as the cutoff for restoring islet cell function, but what is the empirical basis for this? Despite the pivotal implications of this claim and the 79 references cited in this review, there is no reference provided for the reader to verify this claim. What is the current evidence for how long islet cell dysfunction can be reversed before cell death occurs? No doubt individual variation plays a role. How Important? Another question: There is evidence for beta cell regeneration in rodents following calorie restriction, but what is the situation in humans? Current consensus puts human beta cell regenerative turnover at a much lower rate than in rodents, but could this be increased under conditions of altered metabolism, e.g. fasting? Fascinatingly, a research team at Harvard has shown preliminary findings suggesting temporary restoration of insulin secretion in human type 1 diabetics in response to BCG vaccination. A phase 2 clinical trial using this intervention is expected to be completed by July 2020. These preliminary findings are in line with studies showing both enhanced proliferation and apoptosis of beta islet cell populations in mature type 1 diabetics–suggesting that it is not so much that type 1 diabetics have lost all beta islet cells, but that regenerating beta islet cells in these patients are constantly being destroyed:

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Interestingly, there is as much of a 10-fold difference in beta islet cell mass between normal individuals.

How height is related to our health and longevity: a review. Review of eight canonical seems to show that greater height is consistently associated with reduced longevity in each study, despite each employing different methodologies; suggests caloric intake as major determinant of height’s effect on longevity. Short, long-lived people? Think the Sardinians or Okinawans.

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Here is a thread that does a first pass, deep dive exploring this association:

This will be continued in the future.

A recent review by Drs. David Ludwig (a prominent low-carbohydrate diet researcher) and Frank Hu (an important nutritional epidemiologist) at Harvard and Luc Tappy (a notable skeptic of present anti-fructose campaigns) at the University of Lausanne and Jennie Brand-Miller (an important researcher of the glycemic and insulin indices) at the University of Sidney competently covers issues related to carbohydrate quality and reduction: https://www.bmj.com/content/361/bmj.k2340.full The review is well worth reading in full.

A few studies referenced therein are of particular interest:

1. A prospective cohort study showed that replacing saturated fat with low glycemic index carbohydrates (carbohydrates that cause, in the average individual, only a modest increase in blood glucose) decreases heart attack risk, while replacing saturated fat with high glycemic index carbohydrates (carbohydrates that cause, in the average individual, a much greater increase in blood glucose) increases heart attack risk: https://academic.oup.com/ajcn/article/91/6/1764/4597377?ijkey=8bc55b119855b7c1281ca43f026db4e61d222670&keytype2=tf_ipsecsha.

2. An observational study using closed-ended questionnaire, survey dietary assessment, and biomarkers comparing survivors of heart attack to controls in Costa Rica found a dose-response relationship between the ratio of beans to white rice consumed (Costa Ricans consume a traditional bean-and-rice-heavy diet) and cardiometabolic health. In other words, individuals consuming a greater proportion of their carbohydrates from beans were at lower risk than individuals consuming a greater proportion of their carbohydrates from white rice. These findings are consistent with many studies showing the association between bean intake and healthspan and longevity.

If I had to guess, the mechanism at play here would probably be the disruption of cellular and end-organ glucose and energy homeostasis with via excessively energy spikes caused by white rice intake, vis-a-vis the more gradual release of energy seen in legumes. A relevant figure here:

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The study is here: https://academic.oup.com/ajcn/article/94/3/869/4411867?ijkey=9d3429f9edfbc1eaca0f469363507d9dcfc7ed8c&keytype2=tf_ipsecsha.

3. A recent Mendelian randomization study showed a strong genetic relationship between insulin secretory capacity and higher BMI. Mendelian randomization studies are one of the best new tools available for establishing biological causality; for those not familiar, I will do a blog post about this soon. The interesting point about this study is that it supports the hypothesis that high insulin is a causative factor in obesity. Perhaps more interesting, however, is that the reverse relationship was not found. High genetically-determined BMI was not associated with insulin secretion-related SNPs. A reasonable cursory interpretation of these results is that insulin secretion-related SNPs explain only a subset of obese persons, or that while important in contributing to obesity, insulin secretion-related SNPs have a minority causal role. Interestingly, these findings dovetail with discussions in the middle of the 20th century about high-carbohydrate traditional populations; some investigators at the time hypothesized that the robust insulin response to high-carbohydrate meals in these populations was genetically determined and would predispose these people to metabolic syndrome once exposed to the Western diet. This predisposition to metabolic syndrome been borne out in populations such as the Nauru (and many others), who transitioned from a diet high in traditional carbohydrates to the Western diet much higher in fat and refined carbohydrates and now have the highest obesity and diabetes rate in the world. It would be interesting to genetically examine the Nauru and other Polynesian populations to see if insulin-related SNPs are more concentrated in these populations. The Mendelian randomization study showing a causal link between insulin secretion-related SNPs and BMI is here: http://clinchem.aaccjnls.org/content/64/1/192?ijkey=d8f1a92da5cd170b0b918b0003df6dcf4341f32d&keytype2=tf_ipsecsha.

That’s it for today.

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