Glucose and insulin: The key players in longevity plus 6 tips to improve their levels

Highlights:

• Glucose dysregulation is implicated in numerous conditions like diabetes mellitus
• Glucose homeostasis and insulin sensitivity are influenced by factors like physical activity, diet, gut microbiome, and other factors
• Glucose metabolism and insulin are implicated in the aging process
• Glucose can be monitored using invasive, minimally invasive, and non-invasive techniques

Introduction

Glucose monitoring is an effective tool that helps ward off the risk of developing diabetes and its associated complications. Many methods can be utilized to measure blood glucose, both in the long term and in real-time. The hemoglobin A1c (HbA1c) test is considered the standard for long-term measurement of glycemic control. Another way of assessing blood sugar is by wearing a device called a continuous glucose monitor. These popular devices analyze blood sugar levels in real-time while giving the user immediate feedback in response to diet, stress, or any other lifestyle habit.

Glucose metabolism and aging

The aging process is one of the established risk factors for developing many chronic and metabolic diseases, one of which is type 2 diabetes. Therefore, mitigating the effects of aging can positively reflect on the status of many conditions (1). Dysregulation of the glucose metabolism is common with aging, with hyperglycemia (elevated blood glucose) being the most common. Hyperglycemia results from decreased insulin release in response to glucose and/or increased resistance to insulin (1).

The effect of aging on glucose metabolism occurs at various stages, from glucose production to uptake. For example, the efficiency of glucose released by the beta cells in the pancreas is reduced with aging (2). In addition, there is a reduction in insulin’s efficacy that could be attributed to many age-related factors, like reduced physical activity, mitochondrial dysfunction,  increased oxidative stress, and inflammation.

Other key players in glucose regulation and aging include insulin and insulin growth factor-1 (IGF-1) signaling pathways. In humans, defects in the latter were associated with growth issues and cardiovascular diseases, which negatively affect longevity (3). Research has highlighted that lower free IGF-1 plasma levels have been associated with increased lifespan. In the same context, the literature sheds light on the relationship between insulin sensitivity and longevity (4). In a trial by Wijsman et al., the offspring of long-lived siblings had higher whole-body insulin sensitivity than controls. The authors highlighted that peripheral insulin sensitivity, but not hepatic insulin sensitivity, contributes to enhanced longevity. In other words, better peripheral glucose metabolism translates into a more extended lifespan. In addition to the previous, insulin has been mentioned among the target of rapamycin (mTOR) activators, which are implicated in numerous processes like inhibition of autophagy, regulation of mitochondrial function, and glucose metabolism. In addition, it plays a role in the aging process.

Antidiabetic medications, like metformin, have also been found to play a role in aging and lifespan. The said medication belongs to a class of medications called biguanides, which play a role in reducing IGF-1 and improving glucose utilization in humans (5). Evidence supporting the efficacy of metformin has been extensively studied across multiple species. For example. Studies on C. elegans revealed that the larva given buformin (a biguanide) had a 23.4% longer lifespan than controls (5). In Drosophila (fruit fly) model, metformin was found to reduce oxidative stress damage, which is responsible for damaging the DNA and accelerating the aging process. In mice, biguanides were found to prolong the lifespan of mice prone to breast cancer by 21%. In addition, biguanides demonstrated similar positive results on the lifespan in mice models suffering from other diseases, like Huntington's disease (5).

How can glucose homeostasis be maintained with aging?

Research across multiple models has highlighted that maintaining glucoregulatory control is one of the hallmarks of successful aging (1). Glucose homeostasis (factors that help maintain stable glucose levels) can be attained by interventions like caloric restrictions (CR), dietary restriction (DR), and alternate-day fasting (1). CR is defined as reducing caloric intake by 20-40% without causing a nutritional deficiency, while DR refers to withholding or reducing intake of certain types of food (6). These approaches have been found to be beneficial in terms of increasing the lifespan, both in human and animal models.

Another intervention with plausible outcomes toward glucose and insulin regulation is physical activity. Evidence from the literature suggests that physical activity reduces insulin resistance and increases insulin sensitivity (7). In this context, the literature highlights that both aerobic and resistance exercises improve whole-body insulin sensitivity, independent of diet. This effect has been attributed to increased 5' adenosine monophosphate-activated protein kinase (AMPK) (an enzyme that regulates glucose uptake by the muscle), which acts by promoting the activity of glucose transporter type 4 (GLUT4) (an insulin-regulated transporter that increases glucose uptake) (7).

In addition to the previous factors, the gut microbiome has been found to influence glucose metabolism and insulin sensitivity. The gut microbiota plays a role in the secretion of hormones, like glucagon-like peptide 1 (GLP-1) (a hormone that augments the activity of insulin), glucose-dependent insulinotropic peptide (GIP) (a hormone that stimulates the release of insulin from the pancreas), and other hormones (8). In the same context, research has highlighted that even the bacterial composition and ratio impact the release and efficacy of the said hormones. For example, evidence suggests that the gut microbiota has dipeptidyl peptidase IV (DPP-4)-like activity (9). The latter is an enzyme that breaks down GIP and GLP-1. Evidence from the literature revealed that inhibition of the DPP-4 enzyme by administering vildagliptin (an antidiabetic medication) to mice resulted in the modulation of gut bacteria (reduced Oscillibacter and increased abundance of Lactobacillus) (8, 10). Taken together, it demonstrates the role of gut bacteria in regulating host metabolism.

Glucose, insulin, and technology

Glucose monitoring is one of the important interventions that can be utilized to prevent the development of diabetes and related diseases and complications. This, in turn, leads to the prevention of chronic age-related disorders that negatively influence the lifespan (11).It is important to note that the role of continuous glucose monitors is not fully explored in healthy non-diabetic subjects. However, the literature has highlighted its role in understanding how changes in psychological state (stress), body mass index, and other factors can influence daily changes in blood glucose (12). 

Currently, invasive blood glucose level detection methods are heavily used. However, there are limitations related to patient acceptance and impracticality in continuous glucose monitoring techniques (13). On the contrary, non-invasive techniques utilize markers that can be used to measure glucose levels in real-time, like saliva, sweat, tears, and others, without causing any hassle to the wearer (13).  

The use of commercial non-invasive wearable technology has been available for decades. GlucoWatch®, the first wearable device that offered non-invasive technology to monitor blood glucose levels, was approved by the United States Food and Drug Administration (FDA) approximately two decades ago (14, 15). This device offered real-time glucose monitoring functionality by utilizing the technology of reverse iontophoresis. In this process, an electric potential is created between an anode and a cathode that draws Na+ and Cl- ions from the interstitial fluid (fluid found in the spaces around cells) along with glucose. Another example of a similar device that implements non-invasive technologies to measure glucose is Pendra®. The wrist-mounted device measures glucose levels using bioimpedance spectroscopy (14). In this technique, the electric spectrum based on changes in glucose concentrations is measured at a certain wavelength frequency. Other devices utilize non-invasive glucose measurement with other parameters like oxygen saturation. An example is a finger-mounted device, OrSense NBM-200G, which is portable, easy to use, and provides rapid, accurate measurements. The said device employs red near-infrared spectroscopy to measure the blood glucose.

It is important to note that these non-invasive devices do not come without limitations. For example, the devices might produce inaccurate results if there is too much noise due to sweat, disease conditions, changes in body temperature, blood components, humidity, pressure, and other factors (14).

In addition to the previous techniques of glucose monitoring, minimally invasive methods represent alternative monitoring technology. In this method, a biosensor, which measures glucose, is implanted under the skin in a way that allows continuous non-invasive monitoring (16, 17). Examples of these devices is FreeStyle Libre Pro (by Abbott), which measures glucose using interstitial fluid (18). The FDA approved this device in 2017. In this device, the implanted sensor sends information to an external reader that shows the measurements and stores them. In addition, the reader shows the trends (increase and decrease) of glucose measurements (18). Other examples of such devices include Guardian REAL-time (by Medtronic), which uses a subcutaneous sensor to measure glucose levels in the interstitial fluid (17). Despite their feasibility, some limitations, like price, calibration, and sensor lifespan, remain among the challenges.

Tips

• Recommend your clients avoid processed foods containing high amounts of carbohydrates, which negatively influence glucose homeostasis.
• Explain to your clients the importance of CR without malnutrition to improve their glycemic control profile.
• Highlight what DR is and recommend that they implement more fruits, vegetables, and fibers in their diet while reducing consuming nutrients rich in carbohydrates,
• Mention how physical activity and reducing body weight can help them enhance their body’s insulin response, which reflects positively on their lifespan.
• If your client has diabetes, explain how important it is to adhere to medications, physical activity, and dietary recommendations. This is because hyperglycemia or hypoglycemia can accelerate cardiovascular diseases and negatively influence lifespan.
• Explain that continuous glucose monitoring is a good way to monitor glycemic control for patients with diabetes and to prevent the condition in those with prediabetes or otherwise healthy individuals. However, evidence for the latter is limited.

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Conclusions

Glucose dysregulation (increase or decrease) is responsible for developing many conditions. Diabetes mellitus is one of these conditions, which, if not well controlled, could lead to complications and other disorders that shorten the lifespan. Various factors have been identified to influence glucose regulation, such as the gut microbiome, IGF-1, and others. The IGF-1 has also been found to play a role in the aging process, where its elevation negatively influences the lifespan. In addition, research has highlighted the positive outcomes that antidiabetic medications, like metformin, have on longevity. Despite the negative consequences of insulin and glucose homeostasis disturbance, some interventions, like physical activity, diet, and others, have been suggested to mitigate these effects. In addition to preventive factors, glucose monitoring represents a reliable method to identify disturbances in glucose levels. The utilization of technology, like wearable devices, serves as a potential approach that could prolong the lifespan by preventing diabetes through early detection of the disease.   

References

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2.            Kalyani RR, Egan JM. Diabetes and altered glucose metabolism with aging. Endocrinology and Metabolism Clinics. 2013;42(2):333-47.

3.            van Heemst D. Insulin, IGF-1 and longevity. Aging and disease. 2010;1(2):147-57.

4.            Wijsman CA, Rozing MP, Streefland TCM, le Cessie S, Mooijaart SP, Slagboom PE, et al. Familial longevity is marked by enhanced insulin sensitivity. Aging Cell. 2011;10(1):114-21.

5.            Anisimov VN, Semenchenko AV, Yashin AI. Insulin and longevity: antidiabetic biguanides as geroprotectors. Biogerontology. 2003;4(5):297-307.

6.            Trepanowski JF, Canale RE, Marshall KE, Kabir MM, Bloomer RJ. Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: a summary of available findings. Nutrition Journal. 2011;10(1):107.

7.            Bird SR, Hawley JA. Update on the effects of physical activity on insulin sensitivity in humans. BMJ open sport & exercise medicine. 2017;2(1):e000143.

8.            Martin AM, Sun EW, Rogers GB, Keating DJ. The Influence of the Gut Microbiome on Host Metabolism Through the Regulation of Gut Hormone Release. Frontiers in Physiology. 2019;10.

9.            Olivares M, Schüppel V, Hassan AM, Beaumont M, Neyrinck AM, Bindels LB, et al. The Potential Role of the Dipeptidyl Peptidase-4-Like Activity From the Gut Microbiota on the Host Health. Frontiers in Microbiology. 2018;9.

10.          Olivares M, Neyrinck AM, Pötgens SA, Beaumont M, Salazar N, Cani PD, et al. The DPP-4 inhibitor vildagliptin impacts the gut microbiota and prevents disruption of intestinal homeostasis induced by a Western diet in mice. Diabetologia. 2018;61(8):1838-48.

11.          Ristow M, Schmeisser S. Extending life span by increasing oxidative stress. Free radical biology and medicine. 2011;51(2):327-36.

12.          Derosa G, Salvadeo SAT, Mereu R, D'Angelo A, Ciccarelli L, Piccinni MN, et al. Continuous Glucose Monitoring System in Free-Living Healthy Subjects: Results from a Pilot Study. Diabetes Technology & Therapeutics. 2009;11(3):159-69.

13.          Tang L, Chang SJ, Chen C-J, Liu J-T. Non-Invasive Blood Glucose Monitoring Technology: A Review. Sensors (Basel, Switzerland). 2020;20(23):6925.

14.          Vashist SK. Non-invasive glucose monitoring technology in diabetes management: A review. Analytica chimica acta. 2012;750:16-27.

15.          Guk K, Han G, Lim J, Jeong K, Kang T, Lim E-K, et al. Evolution of wearable devices with real-time disease monitoring for personalized healthcare. Nanomaterials. 2019;9(6):813.

16.          The technology | FreeStyle Libre for glucose monitoring | Advice | NICE Nice.org.uk: National Institute for Health and Excellence (NICE); 2017 [updated 2017; cited 2022 10 March]. Available from: https://www.nice.org.uk/advice/mib110/chapter/The-technology.

17.          Yadav J, Rani A, Singh V, Murari BM. Prospects and limitations of non-invasive blood glucose monitoring using near-infrared spectroscopy. Biomedical Signal Processing and Control. 2015;18:214-27.

18.          Blum A. Freestyle Libre Glucose Monitoring System. Clinical diabetes : a publication of the American Diabetes Association. 2018;36(2):203-4.

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