The gut microbiome as possible mediator of the beneficial effects of very low calorie ketogenic diet on type 2 diabetes and obesity: a narrative review.

Several studies have shown a strong correlation between the different types of diets and gut microbiota composition on glycemia and weight loss. In this direction, low-carbohydrate and ketogenic diets have gained popularity, despite studies published so far leading to controversial results on subjects with diabetes. In this narrative review, firstly, we aimed to analyze the role of very-low-calorie ketogenic diets (VLCKDs) in type 2 diabetes (T2DM) and obesity management. Secondly, in this context, we focused attention on gut microbiota as a function of VLCKD, particularly in T2DM and obesity treatment. Finally, we reported all this evidence to underline the importance of gut microbiota to exalt new nutritional strategies for "tailor-made" management, treatment, and rehabilitation in subjects with T2DM and obesity, even with diabetic complications. In conclusion, this narrative review outlined the beneficial impact of VLCKD on gut microbiota even in subjects with T2DM and obesity, and, despite inner VLCKD short-duration feature allowing no sound-enough provisions for long-term outcomes, witnessed in favor of the short-term safety of VLCKD in those patients.Level of evidence Level V: Opinions of authorities, based on descriptive studies, narrative reviews, clinical experience, or reports of expert committees.

Body composition and metabolic changes during a 520-day mission simulation to Mars.

PURPOSE: The "Mars-500 project" allowed to evaluate the changes in psychological/physiological adaptation over a prolonged confinement, in order to gather information for future missions. Here, we evaluated the impact of confinement and isolation on body composition, glucose metabolism/insulin resistance and adipokine levels. METHODS: The "Mars-500 project" consisted of 520 consecutive days of confinement from June 3, 2010 to Nov 4, 2011. The crew was composed of six male subjects (three Russians, two Europeans, and one Chinese) with a median age of 31 years (range 27-38 years). RESULTS: During the 520-day confinement, total body mass and BMI progressively decreased, reaching a significant difference at the end (417 days) of the observation period (- 9.2 and - 5.5%, respectively). Fat mass remained unchanged. A progressive and significant increase of fasting plasma glucose was observed between 249 and 417 days (+ 10/+ 17% vs baseline), with a further increase at the end of confinement (up to + 30%). Median plasma insulin showed a non-significant early increment (60 days; + 86%). Total adiponectin halved (- 47%) 60 days after hatch closure, remaining at this nadir (- 51%) level for a further 60 days. High molecular weight adiponectin remained significantly lower from 60 to 168 days. CONCLUSIONS: Based on these data, countermeasures may be envisioned to balance the potentially harmful effects of prolonged confinement, including a better exercise program, with accurate monitoring of (1) the individual activity and (2) the relationship between body composition and metabolic derangement.

Bioimpedance analysis, metabolic effects and safety of the association Berberis aristata/Bilybum marianum: a 52-week double-blind, placebo-controlled study in obese patients with type 2 diabetes.

Berberine, a quaternary isoquinoline alkaloid present in Berberis aristata, is well known in terms of cholesterol-lowering, hypoglycemic, and insulin sensitizing effects. Because of its low oral bioavailability, to improve intestinal absorption it has been recently combined with silymarin (Silybum marianum). The aim of our placebo controlled study was to evaluate the effects of its association with silymarin on abdominal fat in overweight/obese patients with type 2 diabetes mellitus (T2DM). To do so, 136 obese subjects with T2DM and metabolic syndrome were analyzed for fasting blood glucose and insulin, Insulin Resistance index according to the Homeostatic Model Assessment (HOMA-R), total, HDL and LDL cholesterol, triglycerides, uric acid, BMI, waist circumference, waist to hip ratio and underwent bioelectrical impedance to assess % of abdominal fat. All the above-mentioned parameters, as recorded at enrollment, after 6 months and at the end of the study, had significantly improved in the BBR-treated group in respect to baseline and to the control group. A validated national cardiovascular risk score also improved significantly after BBR treatment in respect to placebo. Our results point to a clinically significant effect in obese people with T2DM and metabolic syndrome. Moreover, for the first time, they provide evidence of a significant uric acid lowering activity as an additive beneficial effect of the association BBR + silymarin.

Unexpected evolution of a monster case of insulin-induced skin lipohypertrophy.

In this journal, in 2020, we published the case of a 74-year-old female outpatient with type-2 diabetes mellitus who self-injected insulin four times a day according to the basal-bolus regimen, with an high glycemic variability and an high rate of severe hypoglycemic episodes. Three years before, we had found two extraordinarily large skin lipohypertrophies, with large underlying fluid collections with high insulin concentration. A long educational and intensive training completely repaired the skin lesions with the disappearance of the subcutaneous insulin reservoirs. Glycemic variability has been reduced dramatically, severe hypoglycemia has almost completely disappeared and the daily dose of insulin has been reduced by 38%. However, this extraordinary, albeit unexpected, result was achieved in five years.

Space Flight-Promoted Insulin Resistance as a Possible Disruptor of Wound Healing.

During space flight, especially when prolonged, exposure to microgravity results in a number of pathophysiological changes such as bone loss, muscle atrophy, cardiovascular and metabolic changes and impaired wound healing, among others. Interestingly, chronic low-grade inflammation and insulin resistance appear to be pivotal events linking many of them. Interestingly, real and experimental microgravity is also associated to altered wound repair, a process that is becoming increasingly important in view of prolonged space flights. The association of insulin resistance and wound healing impairment may be hypothesized from some dysmetabolic conditions, like the metabolic syndrome, type 2 diabetes mellitus and abdominal/visceral obesity, where derangement of glucose and lipid metabolism, greater low-grade inflammation, altered adipokine secretion and adipocyte dysfunction converge to produce systemic effects that also negatively involve wound healing. Indeed, wound healing impairment after traumatic events and surgery in space remains a relevant concern for space agencies. Further studies are required to clarify the molecular connection between insulin resistance and wound healing during space flight, addressing the ability of physical, endocrine/metabolic, and pharmacological countermeasures, as well as nutritional strategies to prevent long-term detrimental effects on tissue repair linked to insulin resistance. Based on these considerations, this paper discusses the pathophysiological links between microgravity-associated insulin resistance and impaired wound healing.

Sex hormones and adipokines in healthy pre-menopausal, post-menopausal and elderly women, and in age-matched men: data from the Brisighella Heart study.

BACKGROUND: Sex hormones and adipokines seem to differently interact in both genders at different ages. AIM: To comparatively evaluate the serum level of adipokines and sex hormones in healthy non-pharmacologically treated premenopausal women, post-menopausal women, and elderly women, and in age-matched men. SUBJECTS: From the historical cohort of the Brisighella Heart Study we selected 199 adult healthy subjects (males: 89; females: 110), aged 62.5±12.4 yr. Men and women included in the age-class subgroups were matched for body mass index (BMI), waist circumference, blood pressure, heart rate, fasting plasma glucose, plasma lipids. RESULTS: Leptin did not differ among various age classes in men, while pre-menopausal women displayed significantly lower serum leptin than post-menopausal women (-6.7 ± 2.2 pg/ml, p=0.036). Post-menopausal women had significantly greater serum leptin when compared with age-matched men (+13.1 ± 2.0 pg/ml, p<0.001); the same was observed for elderly women when compared with elderly men (+11.2 ± 2.3 pg/ml, p<0.001). At any age, women had significantly lower serum testosterone/estrone ratio than age-matched men (p<0.01). Serum DHEAS was inversely proportional to age in both genders. The main predictors of adiponectin level are age in men (p=0.027) and BMI in women (p=0.003). The main predictors of leptin level are BMI and the testosterone/estrone ratio in both sexes (p<0.05). The testosterone/estrone ratio is also the main predictor of ghrelin levels in women (p=0.006). CONCLUSION: Sex hormones and adipokines show specific interactions in the two genders and in different age-classes in a representative sample of adult healthy subjects.

Policaptil Gel Retard in adult subjects with the metabolic syndrome: Efficacy, safety, and tolerability compared to metformin.

BACKGROUND: Policaptil Gel Retard® (PGR), is a new macromolecule complex based on polysaccharides slowing the rate of carbohydrate and fat absorption. It proved to significantly reduce body weight, acanthosis nigricans expression, HbA1c levels, and glucose metabolism abnormalities in obese, hyper-insulinemic adolescents. No such data are available for adults. AIM: to compare the effects of PGR vs. metformin in adult subjects with the Metabolic Syndrome (MS) and T2DM on a Low Glycemic Index diet. SUBJECTS AND METHODS: This spontaneous clinical, longitudinal, single-blind, randomized study based on a per-protocol analysis enrolled 100 outpatients with MS and T2DM consecutively referring to our clinic for three months, and randomly assigned to either the active treatment (Group A:, 6 tablets/day) or the comparator (Group B: Metformin tablets, 1500-2000 mg/day in two divided doses during the two main meals, to minimize side effects) to be taken 30 min before each main meal in equally divided doses. Serum lipid profile, anthropometry, HOMA-IR index, and tolerability parameters were evaluated before and after a 6-month follow-up period. RESULTS: all parameters improved at a similar rate in both groups but for the lipid profile, which got even better in Group A. Group A also experienced less prominent gastrointestinal side effects than its counterpart. CONCLUSION: For the first time, we showed the non-inferiority of PGR compared to metformin in obese adult subjects with the MS and T2DM as for glycemic control and a clear-cut superiority of PGR in terms of both serum lipid-lowering capacity and tolerability.

Technological innovation of Continuous Glucose Monitoring (CGM) as a tool for commercial aviation pilots with insulin-treated diabetes and stakeholders/regulators: A new chance to improve the directives?

Civil aviation pilots who develop insulin-treated diabetes and want to renew a Commercial Pilot License (CPL) represent a medical, social and regulatory problem. This depends on justified concerns about hypoglycemia, the most threatening event for people who carry out jobs requiring a high level of concentration and reliability. This negatively affects social and working aspects of pilots' lives, who have a high profile and a high-cost professional qualification. It could be possible now to revise this attitude thanks to the availability of Continuous Glucose Monitoring (CGM) devices. CGM clearly showed to prevent hypoglycemic events in insulin-treated diabetic patients by allowing strict monitoring and trend prediction of glucose levels. By systematizing available data on such devices and present regulations in CPL issuance worldwide, our review can be used as handy tool for a fruitful discussion among the scientific community, national and international civil aviation regulators, stakeholders and pilots, aimed at evaluating the evidence-based opportunity to revise CPL issuance criteria for insulin-treated diabetic pilots. For the above-mentioned reasons, there are, among the regulatory administrations of Civil Aviation around the globe, several different approaches and limitations set for the subjects with insulin-treated diabetes who want to obtain, or renew, a CPL.

Frailty and muscle metabolism dysregulation in the elderly.

The frailty syndrome is increasingly recognized by geriatricians to identify elders at an extreme risk of adverse health outcomes. The physiological changes that result in frailty are complex and up to now have been extremely difficult to characterize due to the frequent coexistence of acute and chronic illness. Frailty is characterized by an decline in the functional reserve with several alterations in diverse physiological systems, including lower energy metabolism, decreased skeletal muscle mass and quality, altered hormonal and inflammatory functions. This altered network leads to an extreme vulnerability for disease, functional dependency, hospitalization and death. One of the most important core components of the frailty syndrome is a decreased reserve in skeletal muscle functioning which is clinically characterized by a loss in muscle mass and strength (sarcopenia), in walking performance and in endurance associated with a perception of exhaustion and fatigue. There are a number of physiological changes that occur in senescent muscle tissues that have a critical effect on body metabolism. The causes of sarcopenia are multi-factorial and can include disuse, changing hormonal function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. In this review, we will explore the dysregulation of some biological mechanisms that may contribute to the pathophysiology of the frailty syndrome through age-related changes in skeletal muscle mass and function.

HOW to make a mix of low glycemic index flours for a good Neapolitan pizza for patients with diabetes.

BACKGROUND AND AIMS: Our recent data document that a low glycemic index (LGI) Neapolitan pizza prepared with a mix of Kamut and whole wheat flours plus Glucomannan, (i) has a lower impact on postprandial hyperglycemic spikes than pizza made of whole wheat flour, (ii) is pleasant and appreciated as traditional one and (iii) does not cause any gastro-intestinal troubles. The aim of our study was to describe the validation process underlying the identification of the right mix of those elements for a LGI pizza preventing gastro-intestinal disturbances. METHODS: we described all procedures followed to make good products with different combinations of the three components and a series of tests made by four well-experienced professional pasta-making masters, one nutritionist, five diabetologists, one nurse and twenty volunteers with T1DM. RESULTS: we could identify the best workable and most suitable flour mix to achieve both pleasant taste and low glycemic impact proving to be efficient in real-life twin paper providing results from diabetic patients. CONCLUSIONS: this kind of food will certainly help people with diabetes eat pizza without risking any serious deterioration of their own glucose control while fully enjoying socially active life.

Is pizza sutable to type 1 diabetes? A real life identification of best compromise between taste and low glycemic index in patients on insulin pump.

Opposed to whole wheat (WWP), traditional pizza (TP) is loved by patients with type 1 diabetes mellitus (T1DM) despite causing hyperglycemia. 50 well-trained T1DM patients had higher glucose levels after TP than after WWP or mixed flour pizza, which however was tasty, digestible and metabolically appropriate to break diet monotony.

Lessons learned from an unusual case of severe hypoglycemia.

We are hereby reporting on a woman with type 1 diabetes getting insulin, 4 shots a day, and referring to us for an episode of severe hypoglycemia occurred after vigorously rubbing a lipo-hypertrophy (LH). She had always injected insulin into an abdominal LH area but had never suffered from any hypoglycemic event (Hypo) during the last period. Nevertheless her history included frequent Hypos, mostly mild-to-moderate but sometimes severe and eventually ending into unconsciousness and her glycemic control was poor (HbA1c 8.3%, mean FPG 161 ±â€¯22 mg/dl, mean PPG 218 ±â€¯51 mg/dl, glycemic variability (106 ±â€¯44 mg/dl). In fact, all of a sudden she rubbed vigorously the LH area trying to get rid of the abdominal skin thickening and soon after a severe Hypo occurred causing her to need for emergency medical assistance. When back at home, she corrected her technique and carefully refrained from inject insulin into the LH so that after six months the lesion disappeared, glycemic control improved and no Hypo occurred any more. Based on the recent publication reporting on a woman with a large LH consisting of thickened skin surrounding some fluid containing insulin at concentrations 13 fold those in blood, we hypothesize that such severe depended on massive insulin release from rubbed skin stores into the blood stream.

Why are so huge differences reported in the occurrence rate of skin lipohypertrophy? Does it depend on method defects or on lack of interest?

Lipohypertophy (LH) is the most common skin complication of incorrect injection technique which does not only represent an aesthetic defect but also severely disrupts insulin pharmacokinetics/pharmacodynamics. As a consequence of that, hormone release is delayed and unexplained/unpredictable hypoglycemia occurs, both deteriorating metabolic control while negatively affecting adherence to treatment and quality of life. The economic burden due to unwanted intra-LH injections is accounted for by inappropriately high insulin requirements, increased emergency-related hospitalizations, and loss of work days. Greater attention has to be paid by diabetes care teams to education programs with periodic refreshers to achieve better metabolic control and reduce the economic burden of diabetes.

Insulin-induced lypodistrophy in hemodialyzed patients: A new challenge for nephrologists?

Diabetes Mellitus (DM) is the most common cause of renal failure and ESRD all over the world, and often requires an individualized insulin treatment regimen. Malnutrition, depression-related eating behavior changes, high on-off-dialysis day-to-day glycemic variability and frequent hypoglycemic events occurring during or immediately after dialysis make it hard to identify best insulin dosage in hemodialyzed patients. This suggests a prudent attitude including non-stringent control, despite which repeated hypoglycemia quite often occurs in such patients. When looking for possible sources of hypoglycemia, health professionals too often overlook the identification of skin lipodystrophy (LD) due to an incorrect insulin injection technique. This mini-review focuses on the high frequency (57%) of LD in a cohort of 1004 insulin-treated people with DM on dialysis consecutively referring to our joint medical centers, and on its relationship with hypoglycemia and glycemic control/variability. When taking on such patients, care team members accept to face a complex disease burdened with several risk factors requiring high professional skills, and have to keep in mind also the possible presence of any LD areas eventually interfering with expected results. A timely educational intervention on the correct injection technique can help reduce the high risk of hypoglycemia and large glycemic variability in dialysed people with DM.

Skin complications of insulin injections: A case presentation and a possible explanation of hypoglycaemia.

We are willing to report the case of a woman with type 2 diabetes treated with insulin, 4 shots a day, referring to us for 2 very large pigmented abdominal lipo-hypertrophy (LH) areas due to incorrect injection technique. The ultrasound examination showed the presence offluidwithin both LH lesions. Fluid examination showed insulin concentrations 13 times higher thancirculating ones. A12-month longstructured training on correct injection techniques normalized metabolic control and took rid of all sudden severe hypoglycemic episodes and the wide glycemic variability. In fact, both LH areas disappeared became softer and slightly smaller and got fluid-free. This is the first case documenting the presence of sort of an insulin reservoir within LH lesions and fluid reabsorption can explain the disappearance of hypoglycemic episodes and the improvement of glycemic control.

Lispro insulin in people with non-alcoholic liver cirrhosis and type 2 diabetes mellitus.

AIMS: To compare metabolic control under lispro and recombinant regular human insulin (RHI) in people with diet-unresponsive type 2 diabetes mellitus (T2DM) and compensated non-alcoholic liver disease (CLD). METHODS: 108 people with T2DM and CLD were randomly allocated to RHI or lispro according to a 12+12 week cross-over protocol. A 1-week continuous glucose monitoring (CGM) session was performed at the end of each treatment period followed by a standard meal test with a 12IU lispro or RHI shot ahead. RESULTS: CGM showed higher glycemic excursions under RHI than under lispro (p<0.01) with lower glucose levels in the late post-absorption phase (p<0.05) and even more during the night (p<0.01). Post-challenge incremental areas under the curve (ΔAUC) were undistinguishable for insulin but lower for glucose, while insulin peaked higher and earlier and glycemic excursions were lower with lispro than with RHI (0.05

Outcome results of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM.

OBJECTIVE: ACE inhibitors and calcium antagonists may favorably affect serum lipids and glucose metabolism. The primary aim of the Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial (FACET) was to compare the effects of fosinopril and amlodipine on serum lipids and diabetes control in NIDDM patients with hypertension. Prospectively defined cardiovascular events were assessed as secondary outcomes. RESEARCH DESIGN AND METHODS: Inclusion criteria included a diagnosis of NIDDM and hypertension (systolic blood pressure of > 140 mmHg or diastolic blood pressure of > 90 mmHg). Exclusion criteria included a history of coronary heart disease or stroke, serum creatinine > 1.5 mg/dl, albuminuria > 40 micrograms/min, and use of lipid-lowering drugs, aspirin, or antihypertensive agents other than beta-blockers or diuretics. A total of 380 hypertensive diabetics were randomly assigned to open-label fosinopril (20 mg/day) or amlodipine (10 mg/day) and followed for up to 3.5 years. If blood pressure was not controlled, the other study drug was added. RESULTS: Both treatments were effective in lowering blood pressure. At the end of follow-up, between the two groups there was no significant difference in total serum cholesterol, HDL cholesterol, HbA1c, fasting serum glucose, or plasma insulin. The patients receiving fosinopril had a significantly lower risk of the combined outcome of acute myocardial infarction, stroke, or hospitalized angina than those receiving amlodipine (14/189 vs. 27/191; hazards ratio = 0.49, 95% CI = 0.26-0.95). CONCLUSIONS: Fosinopril and amlodipine had similar effects on biochemical measures, but the patients randomized to fosinopril had a significantly lower risk of major vascular events, compared with the patients randomized to amlodipine.