During starvation, fasting, or a diet containing little digestible carbohydrates, the circulating insulin levels are decreased. This promotes lipolysis, and the breakdown of fat becomes the major ...source of energy. The hepatic energy metabolism is regulated so that under these circumstances, ketone bodies are generated from β-oxidation of fatty acids and secreted as ancillary fuel, in addition to gluconeogenesis. Increased plasma levels of ketone bodies thus indicate a dietary shortage of carbohydrates. Ketone bodies not only serve as fuel but also promote resistance to oxidative and inflammatory stress, and there is a decrease in anabolic insulin-dependent energy expenditure. It has been suggested that the beneficial non-metabolic actions of ketone bodies on organ functions are mediated by them acting as a ligand to specific cellular targets. We propose here a major role of a different pathway initiated by the induction of oxidative stress in the mitochondria during increased ketolysis. Oxidative stress induced by ketone body metabolism is beneficial in the long term because it initiates an adaptive (hormetic) response characterized by the activation of the master regulators of cell-protective mechanism, nuclear factor erythroid 2-related factor 2 (Nrf2), sirtuins, and AMP-activated kinase. This results in resolving oxidative stress, by the upregulation of anti-oxidative and anti-inflammatory activities, improved mitochondrial function and growth, DNA repair, and autophagy. In the heart, the adaptive response to enhanced ketolysis improves resistance to damage after ischemic insults or to cardiotoxic actions of doxorubicin. Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors may also exert their cardioprotective action via increasing ketone body levels and ketolysis. We conclude that the increased synthesis and use of ketone bodies as ancillary fuel during periods of deficient food supply and low insulin levels causes oxidative stress in the mitochondria and that the latter initiates a protective (hormetic) response which allows cells to cope with increased oxidative stress and lower energy availability. KEYWORDS: Ketogenic diet, Ketone bodies, Beta hydroxybutyrate, Insulin, Obesity, Type 2 diabetes, Inflammation, Oxidative stress, Cardiovascular disease, SGLT2, Hormesis.
The impact on body weight development is usually analysed by comparing different diet types. Our approach was to change only one component, namely bread, common to most diets. In a single-centre ...triple-blind randomised controlled trial the effects of two different breads on body weight were analyzed without further lifestyle modification. Overweight adult volunteers (
= 80) were randomised 1:1 to exchange previously consumed breads for either a rye bread from milled whole grain (control) or a medium-carbohydrate, low-insulin-stimulating bread (intervention). Pre-tests demonstrated that the two bread types strongly differed in the glucose and insulin response elicited, but had similar energy content, texture and taste. The primary endpoint was the estimated treatment difference (ETD) in change of body weight after 3 months of treatment. Whereas body weight remained unchanged in the control group (-0.1 ± 2.0 kg), significant weight reduction was observed in the intervention group (-1.8 ± 2.9 kg), with an ETD of -1.7 ± 0.2 kg (
= 0.007), that was more pronounced in participants ≥ 55 years (-2.6 ± 3.3 kg), paralleled by significant reductions in body mass index and hip circumference. Moreover, in the intervention group, the percentage of participants with significant weight loss (≥1 kg) was twice as high as in the control group (
< 0.001). No other statistically significant changes in clinical or lifestyle parameters were noted. Simply exchanging a common insulinogenic bread for a low-insulin-stimulating bread demonstrates potential to induce weight loss in overweight persons, especially those at older age.
Insulin shares a limited physiological concentration range with other endocrine hormones. Not only too low, but also too high systemic insulin levels are detrimental for body functions.
The ...physiological function and clinical relevance of insulin are usually seen in association with its role in maintaining glucose homeostasis. However, insulin is an anabolic hormone which stimulates a large number of cellular responses. Not only too low, but also excess insulin concentrations are detrimental to the physiological balance. Although the glucoregulatory activity of insulin is mitigated during hyperinsulinemia by dampening the efficiency of insulin signaling ("insulin resistance"), this is not the case for most other hormonal actions of insulin, including the promotion of protein synthesis, de novo lipogenesis, and cell proliferation; the inhibition of lipolysis, of autophagy-dependent cellular turnover, and of nuclear factor E2-related factor-2 (Nrf2)-dependent antioxidative; and other defense mechanisms. Hence, there is no general insulin resistance but selective impairment of insulin signaling which causes less glucose uptake from the blood and reduced activation of endothelial NO synthase (eNOS). Because of the largely unrestricted insulin signaling, hyperinsulinemia increases the risk of obesity, type 2 diabetes, and cardiovascular disease and decreases health span and life expectancy. In epidemiological studies, high-dose insulin therapy is associated with an increased risk of cardiovascular disease. Randomized controlled trials of insulin treatment did not observe any effect on disease risk, but these trials only studied low insulin doses up to 40 IU/day. Proof for a causal link between elevated insulin levels and cardiovascular disease risk comes from Mendelian randomization studies comparing individuals with genetically controlled low or high insulin production.
The detrimental actions of prolonged high insulin concentrations, seen also in cell culture, argue in favor of a lifestyle that limits circadian insulin levels. The health risks associated with hyperinsulinemia may have implications for treatment regimens used in type 2 diabetes.
Continuous high insulin levels are associated with weight gain and lead to cardiometabolic diseases. Therefore, we have developed the Low-Insulin-Method and integrated it into the multi-component, ...occupational healthcare program SHAPE-AND-MOTION-Medical-Accompanied-Slimming (SAMMAS) to reduce daily insulin levels for long-term weight reduction in overweight or obesity. Employees were randomized into a starting intervention group (SI,
= 15) or waiting list control group (WL,
= 15). SAMMAS consisted of group-based seminars, low-carbohydrate nutrition including formula diet, continuous glucose monitoring, telemetric monitoring, and telemedical coaching. Both groups received telemetric devices at baseline. Intention-to-treat analyses were performed after 12, 26, and 52 weeks. The estimated treatment difference in weight reduction after 12 weeks, which is the primary endpoint of the study, showed a pronounced effect in favour of SI (-6.3 kg with (95% confidence interval) (-7.4; -4.5) (
< 0.001)) after 12 weeks. Furthermore, SI improved fasting blood glucose, HbA1c, quality of life, fasting insulin, blood pressure, and eating behaviour (all
< 0.05) in the within-group analysis, while WL did not. After 26 and 52 weeks, weight reduction could be maintained in the whole group (both groups together) by -6.7 kg (-9.5; -3.8) (
< 0.001) and -6.1 kg (-9.2; -2.7) (
< 0.01). SAMMAS supports clinically relevant weight reduction and long-term weight loss maintenance in individuals with overweight or obesity.
Formula diets can improve glycemic control or can even induce remission in type 2 diabetes. We hypothesized that especially an individualized intense meal replacement by a low-carbohydrate formula ...diet with accompanied self-monitoring of blood glucose (SMBG) contributes to long-term improvements in HbA1c, weight, and cardiometabolic risk factors in poorly controlled type 2 diabetes.
Type 2 diabetes patients were randomized into either a moderate group (M-group) with two meal replacements/day (
= 160) or a stringent group (S-group) with three meal replacements/day (
= 149) during the first week of intervention (1300⁻1500 kcal/day). Subsequently, both groups reintroduced a low-carbohydrate lunch based on individual adaption due to SMBG in weeks 2⁻4. After week 4, breakfast was reintroduced until week 12. During the follow-up period, all of the participants were asked to continue replacing one meal per day until the 52-weeks follow-up. Additionally, an observational control group (
= 100) remained in routine care. Parameters were compared at baseline, after 12 and 52 weeks within and between all of the groups.
321 participants (83%) completed the acute meal replacement phase after 12 weeks and 279 participants (72%) the whole intervention after 52 weeks. Both intervention groups achieved improvements in HbA1c, fasting blood glucose, blood pressure, and weight (all
< 0.001) within 12 weeks. However, these results were not significantly different between both of the intervention groups. The estimated treatment difference in HbA1c reduction was (mean (95% confidence interval CI) -0.10% with 95% CI -0.40; 0.21 also (
> 0.05) (S-group vs. M-group) not statistically different after 12 weeks. However, only the S-group showed a clinically relevant improvement in HbA1c of -0.81% -1.06; -0.55 (
< 0.001) after 52 weeks of follow-up, whereas HbA1c was not statistically different between the M- and control group.
Individualized meal replacement with SMBG demonstrated beneficial effects on HbA1c and cardiometabolic parameters in type 2 diabetes. Furthermore, the initiation of a weight loss program with one week of full meal replacement (three meals per day) resulted in a clinically relevant long-term HbA1c reduction, as compared to an observational control group that had standard care.
Lifestyle interventions including meal replacement are suitable for prevention and treatment of obesity and type-2-diabetes. Since leptin is involved in weight regulation, we hypothesised that a meal ...replacement-based lifestyle intervention would reduce leptin levels more effectively than lifestyle intervention alone. In the international, multicentre, randomised-controlled ACOORH-trial (Almased-Concept-against-Overweight-and-Obesity-and-Related- Health-Risk), overweight or obese participants with metabolic syndrome criteria (n = 463) were randomised into two groups and received telemonitoring devices and nutritional advice. The intervention group additionally used a protein-rich, low-glycaemic meal replacement. Data were collected at baseline, after 1, 3, 6, and 12 months. All datasets providing leptin data (n = 427) were included in this predefined subanalysis. Serum leptin levels significantly correlated with sex, body mass index, weight, and fat mass at baseline (p < 0.0001). Stronger leptin reduction has been observed in the intervention compared to the control group with the lowest levels after 1 month of intervention (estimated treatment difference −3.4 µg/L 1.4; 5.4 for females; −2.2 µg/L 1.2; 3.3 for males; p < 0.001 each) and was predictive for stronger reduction of body weight and fat mass (p < 0.001 each) over 12 months. Strongest weight loss was observed after 6 months (−5.9 ± 5.1 kg in females of the intervention group vs. −2.9 ± 4.9 kg in the control group (p < 0.0001); −6.8 ± 5.3 kg vs. −4.1 ± 4.4 kg (p = 0.003) in males) and in those participants with combined leptin and insulin decrease. A meal replacement-based lifestyle intervention effectively reduces leptin which is predictive for long-term weight loss.
Lifestyle interventions have been shown to reverse hyperglycemia to normoglycemia. However, these effects are not long-lasting and are accompanied with high dropout rates. As formula diets have been ...shown to be simple in usage and effective in improving glycemic control, we hypothesised that adding a low-carbohydrate and energy deficit formula diet to a low-intensity lifestyle intervention is superior in reversing prediabetes compared with lifestyle intervention alone. In this predefined subanalysis of an international, multicenter randomised controlled trial (
(ACOORH) study (ID DRKS00006811)), 141 persons with prediabetes were randomised (1:2) into either a control group with lifestyle intervention only (CON,
= 45) or a lifestyle intervention group accompanied with a formula diet (INT,
= 96). Both groups were equipped with telemonitoring devices. INT received a low-carbohydrate formula diet substituting three meals/day (~1200 kcal/day) within the first week, two meals/day during week 2-4, and one meal/day during week 5-26 (1300-1500 kcal/day). Follow-up was performed after 52 weeks and 105 participants (75%, INT:
= 74; CON:
= 31) finished the 26-week intervention phase. Follow-up data after 52 weeks were available from 93 participants (66%, INT:
= 65; CON:
= 28). Compared with CON, significantly more INT participants converted to normoglycemia after 52 weeks (50% vs. 31%;
< 0.05). The risk reduction led to a number-needed-to-treat of 5.3 for INT. Lifestyle intervention with a low-carbohydrate formula diet reduces prediabetes prevalence stronger than lifestyle intervention alone and is effective for type 2 diabetes prevention.
Self-monitoring of blood glucose using capillary glucose testing (C) has a number of shortcomings compared to continuous glucose monitoring (CGM). We aimed to compare these two methods and used blood ...glucose measurements in venous blood (IV) as a reference. Postprandial blood glucose levels were measured after 50 g oral glucose load and after the consumption of a portion of different foods containing 50 g of carbohydrates. We also evaluated the associations between postprandial glucose responses and the clinical characteristics of the participants at the beginning of the study.
12 healthy volunteers (age: 36 ± 17 years, BMI: 24.9 ± 3.5 kg/m²) ate white bread (WB) and whole grain (WG) bread and drank a 50 g glucose drink as reference. Postprandial glucose responses were evaluated by CGM, IV and C blood glucose measurements. Incremental area under the curve (AUC
) of postprandial blood glucose was calculated for 1 h (AUC
) and 2 h (AUC
).
After the consumption of white bread and whole grain bread, the AUC
did not differ between CGM and IV or C. AUC
of CGM showed no difference compared to C. Correlation analyses revealed a positive association of age with glucose AUC
(
= 0.768;
= 0.004) and WG AUC
(
= 0.758;
= 0.004); fasting blood glucose correlated with WG AUC
(
= 0.838;
< 0.001).
Despite considerable inter-individual variability of postprandial glycemic responses, CGM evaluated postprandial glycemic excursions which had comparable results compared to standard blood glucose measurements under real-life conditions. Associations of AUC
and AUC
postprandial glucose response with age or fasting blood glucose could be shown.
Although meal replacement can lead to weight reduction, there is uncertainty whether this dietary approach implemented into a lifestyle programme can improve long-term dietary intake. In this ...subanalysis of the
(ACOORH) study (
= 463), participants with metabolic risk factors were randomly assigned to either a meal replacement-based lifestyle intervention group (INT) or a lifestyle intervention control group (CON). This subanalysis relies only on data of participants (
= 119) who returned correctly completed dietary records at baseline, and after 12 and 52 weeks. Both groups were not matched for nutrient composition at baseline. These data were further stratified by sex and also associated with weight change. INT showed a higher increase in protein intake related to the daily energy intake after 12 weeks (+6.37% 4.69; 8.04 vs. +2.48% 0.73; 4.23,
< 0.001) of intervention compared to CON. Fat and carbohydrate intake related to the daily energy intake were more strongly reduced in the INT compared to CON (both
< 0.01). After sex stratification, particularly INT-women increased their total protein intake after 12 (INT: +12.7 g vs. CON: -5.1 g,
= 0.021) and 52 weeks (INT: +5.7 g vs. CON: -16.4 g,
= 0.002) compared to CON. Protein intake was negatively associated with weight change (r = -0.421;
< 0.001) after 12 weeks. The results indicate that a protein-rich dietary strategy with a meal replacement can improve long-term nutritional intake, and was associated with weight loss.
While obesity impairs health-related quality of life (HRQOL), lifestyle interventions targeting weight reduction have been effective in improving HRQOL. Therefore, we hypothesised that a meal ...replacement-based lifestyle intervention, which has been shown to successfully reduce weight, would also improve HRQOL more effectively than a lifestyle intervention alone. In the international, multicenter, randomised-controlled ACOORH-trial (Almased-Concept-against- Overweight-and-Obesity-and-Related-Health-Risk), overweight or obese participants with elevated risk for metabolic syndrome (n = 463) were randomised into two groups. Both groups received telemonitoring devices and nutritional advice. The intervention group additionally used a protein-rich, low-glycaemic meal replacement for 6 months. HRQOL was estimated at baseline, after 3 and 12 months, using the SF-36 questionnaire, and all datasets providing HRQOL data (n = 263) were included in this predefined subanalysis. Stronger improvements in the physical component summary (PCS) were observed in the intervention compared to the control group, peaking after 3 months (estimated treatment difference 2.7 1.2; 4.2; p < 0.0001), but also in the long-term. Multiple regression analysis demonstrated that insulin levels and the achieved weight loss were associated with the mental component summary (MCS) after 12 months (p < 0.05). Thus, meal replacement-based lifestyle intervention is not only effective in weight reduction but, concomitantly, in enhancing HRQOL.
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