Calorie Restriction: Glucose Control is Vital!

Those who follow calorie restriction the CR Way know that blood glucose control is emphasized (see Chapter 4, for example, “Glucose Control: The Sweet Spot in Longevity”). While many search for a drug to mimic the effects of CR or to increase CR’s age-slowing effect, turn around, Dorothy, and click your heels three times because a natural way to increase CR benefits has been readily available for years – Keep Glucose Low!

The benefits of low glucose are so profound that they are documented throughout  and include –

  • Increased energy
  • Increased protection from cancer
  • Increased cognitive ability
  • Better eyesight
  • Increased protection from heart disease
  • Increased protection from diabetes
  • Increased expression of longevity genes

Meanwhile, glucose control is also important to reduce formation of AGEs (Advanced Glycation Endproducts) — a potential side effect of long-term CR, practiced without the CR Way approach of gently teasing insulin into production. In a groundbreaking study, CR research  greats – Luigi Fontana, Samuel Klein, and John O. Holloszy, found that 40% of those practicing long-term calorie restriction were not producing enough insulin to easily dispose of the  bolus of glucose, which is poured down the throat of unfortunate individuals who undergo a standard glucose tolerance test [Oral Glucose Tolerance Test (OGTT)] includes measuring blood glucose levels in a fasting state, and at prescribed intervals before and after oral glucose intake (75 or 100 g) or intravenous infusion (0.5 g/kg). It is supposed to be a test to determine the ability of an individual to maintain homeostasis of blood glucose. However, when people who intentionally ingest very little sugar and other food that is digested quickly to glucose and therefore secrete very little insulin – only what is required for their small sugar intake – are given this test, the glucose floods their systems, leading to the opposite of homeostasis and providing no useful data. Fructosamine, a marker of AGE formation, was higher in this group.

Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action,
and adipokine production. 

Luigi Fontana, Samuel Klein, John O. Holloszy
Age (Dordr). 2010 Mar;32(1):97-108. Epub 2009 Nov 11.

Calorie restriction (CR) slows aging and is thought to improve insulin sensitivity in laboratory animals. In contrast, decreased insulin signaling and/or mild insulin resistance paradoxically extends maximal lifespan in various genetic animal models of longevity.

Nothing is known regarding the long-term effects of CR on glucose tolerance and insulin action in lean healthy humans. In this study we evaluated body composition, glucose, and insulin responses to an oral glucose tolerance test and serum adipokines levels in 28 volunteers, who had been eating a CR diet for an average of 6.9±5.5 years, (mean age 53.0±11 years), in 28 age-, sex-, and body fat-matched endurance runners (EX), and 28 age- and sex-matched sedentary controls eating Western diets (WD).

We found that the CR and EX volunteers were significantly leaner than the WD volunteers. Insulin sensitivity, determined according to the HOMA-IR and the Matsuda and DeFronzo insulin sensitivity indexes, was significantly higher in the CR and EX groups than in the WD group (P=0.001). Nonetheless, despite high serum adiponectin and low inflammation, approximately 40% of CR individuals exhibited an exaggerated hyperglycemic response to a glucose load.

This impaired glucose tolerance is associated with lower circulating levels of IGF-1, total testosterone, and triiodothyronine, which are typical adaptations to life-extending CR in rodents.

PMID: 19904628

From the full-text of the paper:

Aging and many age-associated diseases in both humans and rodents are associated with progressive increase in fasting insulin concentration and insulin resistance (Meigs et al. 2003; Basu et al. 2003; Reaven 1995). However, the relationship between aging/aging related diseases and insulin resistance is confounded by associated factors such as excessive abdominal adiposity, decreased physical activity, hyperinsulinemia, dyslipidemia, inflammation, and other metabolic and hormonal components of the metabolic syndrome (Barzilai et al. 1998; Reaven 1995).

It is intriguing that based on the 2-h OGTT plasma glucose values, 11 of our CR subjects met diagnostic criteria for glucose intolerance (Genuth et al. 2003), and six of the CRNGT subjects had high–normal 2-h glucose values, even though all CR subjects were extremely lean and had very low fasting plasma concentrations of glucose and insulin, and an outstanding metabolic profile (very low triglyceride, high HDL-cholesterol, high adiponectin, and extremely low C-reactive protein concentrations; Fontana et al. 2006).”

All of these markers are associated with increased longevity and protection from disease. In fact, Table 4 below, excerpted from the study, shows that those who were not able to dispose of the glucose influx easily (CR-IGT) had better scores on key markers – testosterone, adiponectin, IGF-I than the CR group that did well in the glucose tolerance test (CR -EGT) . It is likely that the CR – EGT group consumed a high protein diet, which would explain the extraordinarily high IGF-I scores at the high end of the reference range. For more see High Protein Negates key Longevity Marker.


Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production

Luigi Fontana, Samuel Klein, John O. Holloszy - ©American Aging Association 2009, Epub


Some speculate that the long-term CR group had “insulin resistance,” a condition in which the body produces insulin, but doesn’t use it properly. The paper states:

“decreased insulin sensitivity and glucose disposal could enhance survival, by preventing hypoglycemia and maintaining circulating glucose for organs that require glucose as a fuel.”

We think that rather than decreased insulin sensitivity, we are simply seeing decreased insulin production, a goal of long-term calorie restriction – as increased  insulin production is associated with decreased longevity and increased cancer, diabetes, and both heart and Alzheimer’s diseases.

In fact, a standard oral glucose test is probably not appropriate to judge insulin secretion in a normal healthy calorie restrictor. Looking at the activity level of glucagon– the glucose-maintaining hormone, produced by pancreatic a cells when calorie intake is low would be more informative.

Prevention of AGE formation

While decreased insulin production is likely to be vital for CR benefits, having little insulin around to dispose of glucose could result in increased formation of AGEs (Advanced Glycation Endproducts) – biological garbage that has many deleterious effects.  Because of this, The CR Way  recommends the tease meal: to start the huge metabolic shift from fasting when growth operations powered by insulin are more quiescent to insulin production, allowing the body to deal effectively with circulating glucose.

For tease meal suggestions see

  • Paul McGlothin & Meredith Averill. The CR Way, NY: HarperCollins, 2008, pp. 191-194
  • The CR Way to Happy Dieting, available to Longevity Level members of
  • “Lentil Tomato Tease” under recipes in the NutriBase CR Way Edition Software. Note that the software makes it easy to plan tease meals, which have a separate section in the food log and a tracking section for charting of glucose effects
  • To get a head start on glucose control find out more about The CR Way to Great Glucose Control


Barzilai N, Banerjee S, Hawkins M, Chen W, Rossetti L
Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat.
The Journal of Clinical Investigation. 1998 Apr 1;101(7):1353-61.
PMID: 9525977

Basu R, Breda E, Oberg AL, Powell CC, Dalla Man C, Basu A, Vittone JL, Klee GG, Arora P, Jensen MD, Toffolo G, Cobelli C, Rizza RA
Mechanisms of the age-associated deterioration n glucose tolerance: contribution of alterations in insulin secretion, action, and clearance.
Diabetes. 2003 Jul;52(7):1738-48.
PMID: 12829641

Meigs JB, Muller DC, Nathan DM, Blake DR, Andres R, Baltimore Longitudinal Study of Aging
The natural history of progression from normal glucose tolerance to type 2 diabetes in the Baltimore Longitudinal Study of Aging.
Diabetes. 2003 Jun;52(6):1475-84.
PMID: 12765960

Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, Kitzmiller J, Knowler WC, Lebovitz H, Lernmark A, Nathan D, Palmer J, Rizza R, Saudek C, Shaw J, Steffes M, Stern M, Tuomilehto J, Zimmet P; Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.
Follow-up report on the diagnosis of diabetes mellitus.
Diabetes Care. 2003 Nov;26(11):3160-7.
PMID: 14578255

Reaven GM
Pathophysiology of insulin resistance in human disease.
Physiological Reviews. 1995 Jul;75(3):473-86. Review.
PMID: 7624391

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