Obese visceral fat tissue inflammation: from protective to detrimental?

Obesity usually is accompanied by inflammation of fat tissue, with a prominent role of visceral fat. Chronic inflammation in obese fat tissue is of a lower grade than acute immune activation for clearing the tissue from an infectious agent. It is the loss of adipocyte metabolic homeostasis that causes activation of resident immune cells for supporting tissue functions and regaining homeostasis. Initially, the excess influx of lipids and glucose in the context of overnutrition is met by adipocyte growth and proliferation. Eventual lipid overload of hypertrophic adipocytes leads to endoplasmic reticulum stress and the secretion of a variety of signals causing increased sympathetic tone, lipolysis by adipocytes, lipid uptake by macrophages, matrix remodeling, angiogenesis, and immune cell activation. Pro-inflammatory signaling of adipocytes causes the resident immune system to release increased amounts of pro-inflammatory and other mediators resulting in enhanced tissue-protective responses. With chronic overnutrition, these protective actions are insufficient, and death of adipocytes as well as senescence of several tissue cell types is seen. This structural damage causes the expression or release of immunostimulatory cell components resulting in influx and activation of monocytes and many other immune cell types, with a contribution of stromal cells. Matrix remodeling and angiogenesis is further intensified as well as possibly detrimental fibrosis. The accumulation of senescent cells also may be detrimental via eventual spread of senescence state from affected to neighboring cells by the release of microRNA-containing vesicles. Obese visceral fat inflammation can be viewed as an initially protective response in order to cope with excess ambient nutrients and restore tissue homeostasis but may contribute to tissue damage at a later stage.

Ketone bodies: from enemy to friend and guardian angel.

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 ß-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.

Insulin: too much of a good thing is bad.

BACKGROUND: 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. MAIN BODY: 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. CONCLUSIONS: 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.

Chaperones may cause the focus of diabetes autoimmunity on distinct (pro)insulin peptides.

It is still an enigma why T cell autoreactivity in type 1 diabetes targets few beta cell antigens only. Among these, one primary autoantigen is pro(insulin). Autoimmune T cells preferentially recognise three epitopes on the proinsulin molecule, of which the peptide region B:11-23 is the dominant one. Interestingly, the three regions superimpose with binding sites of the chaperone hsp70, the region B:11-23 being the strongest binding one. Absence of an intact core region B:15-17 prevents autoimmune diabetes in NOD as well as binding of hsp70. A role of hsp70 in selecting autoimmune epitopes is supported by the ability of this and other chaperones to deliver bound peptides to MHC class I and II molecules for efficient antigen presentation. Binding of hsp70 to receptors on antigen presenting cells such as TLR4 results in costimulatory signals for T cell activation. Strongest effects are seen for the mixture of hsp70 with the peptide B:11-23. Thus, hsp70 may assist in proinsulin epitope selection and efficient presentation to autoreactive T cells. The concept of chaperone guided immune reactivity may also apply to other autoimmune diseases.

Insulin translates unfavourable lifestyle into obesity.

Lifestyle factors conferring increased diabetes risk are associated with elevated basal insulin levels (hyperinsulinaemia). The latter predicts later obesity in children and adolescents.A causal role of hyperinsulinaemia for adipose tissue growth is probable because pharmacological reduction of insulin secretion lowers body weight in people who are obese. Genetic inactivation of insulin gene alleles in mice also lowers their systemic insulin levels and prevents or ameliorates high-fat diet-induced obesity. Hyperinsulinaemia causes weight gain because of a physiological property of insulin. Insulin levels that are on the high side of normal, or which are slightly elevated, are sufficient to suppress lipolysis and promote lipogenesis in adipocytes. The effect of insulin on glucose transport or hepatic glucose production requires six or two times higher hormone levels, respectively.It seems justified to suggest a lifestyle that avoids high insulin levels in order to limit anabolic fat tissue activity.

Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes.

BACKGROUND: Environmental and lifestyle changes, in addition to the ageing of populations, are generally believed to account for the rapid global increase in type 2 diabetes prevalence and incidence in recent decades. DISCUSSION: In this review, we present a comprehensive overview of factors contributing to diabetes risk, including aspects of diet quality and quantity, little physical activity, increased monitor viewing time or sitting in general, exposure to noise or fine dust, short or disturbed sleep, smoking, stress and depression, and a low socioeconomic status. In general, these factors promote an increase in body mass index. Since loss of ß-cell function is the ultimate cause of developing overt type 2 diabetes, environmental and lifestyle changes must have resulted in a higher risk of ß-cell damage in those at genetic risk. Multiple mechanistic pathways may come into play. CONCLUSIONS: Strategies of diabetes prevention should aim at promoting a 'diabetes-protective lifestyle' whilst simultaneously enhancing the resistance of the human organism to pro-diabetic environmental and lifestyle factors. More research on diabetes-protective mechanisms seems warranted.

Cardiometabolic effects of two coffee blends differing in content for major constituents in overweight adults: a randomized controlled trial.

PURPOSE: The hypothesis was tested that coffee types differing in content of major constituents also differ with regard to cardiometabolic effects. METHODS: Overweight persons (n = 118) were randomized to consume a dark roast [rich in N-methylpyridinium (NMP)] or medium roast (rich in caffeoylquinic acids, trigonelline) coffee blend for 3 months, after a washout period of 4 weeks. Before and after the intervention period, body weight and 15 further general and biochemical parameters were determined. RESULTS: Participants consumed an average of 4-5 cups per day. Mean body weight, body mass index and waist circumference did not change during the coffee consumption phase in either of the study groups. Systolic blood pressure decreased in the dark roast coffee group only (p < 0.05). High-density lipoprotein cholesterol levels increased in the medium roast coffee group only, and triglyceride levels increased in the dark roast coffee group only. Glucoregulation and insulin levels were not affected, although there was a small increase of hemoglobin A1c values in both groups. An increase of adiponectin levels occurred in the medium roast coffee group only and was negatively associated with NMP concentrations. Differences did not remain statistically significant after correction for multiple testing. CONCLUSIONS: Medium and dark roast coffee blends exert small but possibly relevant different cardiometabolic effects. Further studies of health outcomes in relation to coffee constituents seem warranted.

Serum adipokines as biomarkers of beta-cell function in patients with type 1 diabetes: positive association with leptin and resistin and negative association with adiponectin.

BACKGROUND: We investigated the adipokines adiponectin, leptin and resistin as serum biomarkers of beta-cell function in patients with type 1 diabetes. METHODS: One hundred and eighteen patients with type 1 diabetes (20.3 ± 7.5 years) diagnosed <5 years underwent standardized mixed meal test (MMTT) for 2 h. Systemic concentrations of C-peptide, adiponectin, leptin and resistin obtained during MMTT were measured and compared between patient groups by multiple regression analysis. RESULTS: Patients were divided by their adipokine levels in subgroups above or below the median level ('high versus low'). High adiponectin levels (>10.6 µg/mL) were associated with lower C-peptide compared to the low adiponectin subgroup (p < 0.03). Increased leptin or resistin concentrations associated positively with beta-cell function even after adjustment for metabolic confounders (p < 0.04). The described associations between adipokines and C-peptide concentrations persisted in Spearman correlation tests (p < 0.05). Serum adipokines fell during MMTT (p < 0.05). CONCLUSIONS: Serum adipokine levels differentially correlate with beta-cell function in type 1 diabetes independent of BMI or metabolic control. Serum adipokines should be investigated as biomarkers of beta-cell function in prospective studies and intervention trials in type 1 diabetes.

Insulin and aging - a disappointing relationship.

Experimental studies in animal models of aging such as nematodes, fruit flies or mice have observed that decreased levels of insulin or insulin signaling promotes longevity. In humans, hyperinsulinemia and concomitant insulin resistance are associated with an elevated risk of age-related diseases suggestive of a shortened healthspan. Age-related disorders include neurodegenerative diseases, hypertension, cardiovascular disease, and type 2 diabetes. High ambient insulin concentrations promote increased lipogenesis and fat storage, heightened protein synthesis and accumulation of non-functional polypeptides due to limited turnover capacity. Moreover, there is impaired autophagy activity, and less endothelial NO synthase activity. These changes are associated with mitochondrial dysfunction and oxidative stress. The cellular stress induced by anabolic activity of insulin initiates an adaptive response aiming at maintaining homeostasis, characterized by activation of the transcription factor Nrf2, of AMP activated kinase, and an unfolded protein response. This protective response is more potent in the long-lived human species than in short-lived models of aging research resulting in a stronger pro-aging impact of insulin in nematodes and fruit flies. In humans, resistance to insulin-induced cell stress decreases with age, because of an increase of insulin and insulin resistance levels but less Nrf2 activation. These detrimental changes might be contained by adopting a lifestyle that promotes low insulin/insulin resistance levels and enhances an adaptive response to cellular stress, as observed with dietary restriction or exercise.

Impact of a Low-Insulin-Stimulating Bread on Weight Development-A Real Life Randomised Controlled Trial.

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 (n = 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 (p = 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 (p < 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.

Cellular interferon-γ and interleukin-13 immune reactivity in type 1, type 2 and latent autoimmune diabetes: action LADA 6.

OBJECTIVE: Type 1 diabetes and latent autoimmune diabetes in adults (LADA) are thought to result from immune-mediated ß-cell destruction. It remains unclear why LADA is clinically less severe compared to type 1 diabetes. This study aimed to compare the pro-inflammatory (interferon-γ, IFN-γ) and anti-inflammatory (interleukin-13, IL-13) T-cell responses in humans with LADA and type 1 diabetes. RESEARCH DESIGN AND METHODS: IFN-γ and IL-13 T-cell responses to a panel of 16 (auto)-antigens were tested using an enzyme linked immune-spot technique and peripheral T-cells from 35 patients with type 1 diabetes, 59 patients with type 2 diabetes, 23 LADA patients, and 42 control subjects. RESULTS: LADA and type 1 diabetes patients did not display any statistically significant differences in the frequency of IFN-γ or IL-13 responses to auto-antigenic stimuli, positive control or mitogen. Overall very low T cell reactivity to autoantigens was detected in all groups. IL-13 responses but not IFN-γ responses to recall antigen tetanus toxoid were higher in healthy control subjects compared to patients with type 1 or type 2 diabetes or LADA (P<0.05). Diabetes, independent of type, was associated with weaker response to recall antigen tetanus toxoid. CONCLUSIONS: LADA patients are indistinguishable from type 1 diabetes patients for cellular IFN-γ and IL-13 responses upon mitogen and recall antigen stimulation. These results extend previous findings showing that systemic cytokine/chemokine and humoral responses in type 1 diabetes and LADA are similar.

Dietary factors and low-grade inflammation in relation to overweight and obesity.

Low-grade inflammation is a characteristic of the obese state, and adipose tissue releases many inflammatory mediators. The source of these mediators within adipose tissue is not clear, but infiltrating macrophages seem to be especially important, although adipocytes themselves play a role. Obese people have higher circulating concentrations of many inflammatory markers than lean people do, and these are believed to play a role in causing insulin resistance and other metabolic disturbances. Blood concentrations of inflammatory markers are lowered following weight loss. In the hours following the consumption of a meal, there is an elevation in the concentrations of inflammatory mediators in the bloodstream, which is exaggerated in obese subjects and in type 2 diabetics. Both high-glucose and high-fat meals may induce postprandial inflammation, and this is exaggerated by a high meal content of advanced glycation end products (AGE) and partly ablated by inclusion of certain antioxidants or antioxidant-containing foods within the meal. Healthy eating patterns are associated with lower circulating concentrations of inflammatory markers. Among the components of a healthy diet, whole grains, vegetables and fruits, and fish are all associated with lower inflammation. AGE are associated with enhanced oxidative stress and inflammation. SFA and trans-MUFA are pro-inflammatory, while PUFA, especially long-chain n-3 PUFA, are anti-inflammatory. Hyperglycaemia induces both postprandial and chronic low-grade inflammation. Vitamin C, vitamin E and carotenoids decrease the circulating concentrations of inflammatory markers. Potential mechanisms are described and research gaps, which limit our understanding of the interaction between diet and postprandial and chronic low-grade inflammation, are identified.

Coffee and Lower Risk of Type 2 Diabetes: Arguments for a Causal Relationship.

Prospective epidemiological studies concur in an association between habitual coffee consumption and a lower risk of type 2 diabetes. Several aspects of these studies support a cause-effect relationship. There is a dependency on daily coffee dose. Study outcomes are similar in different regions of the world, show no differences between sexes, between obese versus lean, young versus old, smokers versus nonsmokers, regardless of the number of confounders adjusted for. Randomized controlled intervention trials did not find a consistent impact of drinking coffee on acute metabolic control, except for effects of caffeine. Therefore, lowering of diabetes risk by coffee consumption does not involve an acute effect on the post-meal course of blood glucose, insulin or insulin resistance. Several studies in animals and humans find that the ingestion of coffee phytochemicals induces an adaptive cellular response characterized by upregulation and de novo synthesis of enzymes involved in cell defense and repair. A key regulator is the nuclear factor erythroid 2-related factor 2 (Nrf2) in association with the aryl hydrocarbon receptor, AMP-activated kinase and sirtuins. One major site of coffee actions appears to be the liver, causing improved fat oxidation and lower risk of steatosis. Another major effect of coffee intake is preservation of functional beta cell mass via enhanced mitochondrial function, lower endoplasmic reticulum stress and prevention or clearance of aggregates of misfolded proinsulin or amylin. Long-term preservation of proper liver and beta cell function may account for the association of habitual coffee drinking with a lower risk of type 2 diabetes, rather than acute improvement of metabolic control.

The Epidemiological Boehringer Ingelheim Employee Study (Part 3): Association of Elevated Fasting Insulin Levels but Not HOMA-IR With Increased Intima Media Thickness and Arteriosclerosis in Middle-Aged Persons.

Background: Recently published genetic studies have indicated a causal link between elevated insulin levels and cardiovascular disease (CVD) risk. We, therefore, hypothesized that increased fasting insulin levels are also associated with precursors of CVD such as endothelial lesions. Methods: Middle-aged (≥40 years, n = 1,639) employees were followed up for the occurrence of increased intima media thickness (IMT ≥ 1 mm) or plaques in abdominal or cervical arteries (arteriosclerosis). Multivariable logistic regression analyses determined the incidence of increased IMT or arteriosclerosis. Adjusted relative risk (ARR) for increased IMT and arteriosclerosis was calculated by using Mantel-Haenszel analysis. Results: Increased IMT was diagnosed in 238 participants (15 %) and 328 (20 %) developed arteriosclerosis after 5 years of follow-up. Logistic regression analysis identified fasting insulin, BMI and smoking as risk factors for both cardiovascular endpoints (all p < 0.05), whereas age and diastolic blood pressure were risk factors for increased IMT only, and male sex was associated with incident arteriosclerosis only (all p < 0.01). Additional adjustment for BMI change during follow-up did not modify these associations (including fasting insulin), but adjustment for fasting insulin change during follow-up removed BMI as risk factor for both cardiovascular endpoints. Fasting insulin change during follow-up but not BMI change associated with increased IMT and arteriosclerosis (both p < 0.001). ARR analysis indicated that high fasting insulin and BMI added to age and sex as risk factors. Homeostatic model assessment of insulin resistance (HOMA-IR) did not associate with either cardiovascular endpoint in any model and smoking did not increase the risk conferred by high fasting insulin levels. Conclusions: Higher fasting insulin levels and increases in fasting insulin over time are associated with atherogenic progression and supersede BMI as well as HOMA-IR as risk factors.

Association of T-cell reactivity with beta-cell function in recent onset type 1 diabetes patients.

OBJECTIVE: The aim of the current study was to investigate whether autoantigen directed T-cell reactivity relates to beta-cell function during the first 78 weeks after diagnosis of type 1 diabetes. RESEARCH DESIGN AND METHODS: 50 adults and 49 children (mean age 27.3 and 10.9 years respectively) with recent onset type 1 diabetes who participated in a placebo-controlled trial of immune intervention with DiaPep277 were analyzed. Secretion of interferon (IFN)-gamma, interleukin (IL)-5, IL-13 and IL-10 by single peripheral mononuclear cells (PBMC) upon stimulation with islet antigens GAD65, heat shock protein 60 (Hsp60) protein-tyrosine-phosphatase-like-antigen (pIA2) or tetanus toxoid (TT) was determined applying ELISPOT; beta-cell function was evaluated by glucagon stimulated C-peptide. Multivariate regression analysis was applied. RESULTS: In general, number of islet antigen-reactive cells decreased over 78 weeks in both adults and children, whereas reactivity to TT was not reduced. In addition, there was an association between the quality of immune cell responses and beta-cell function. Overall, increased responses by IFN-gamma secreting cells were associated with lower beta-cell function whereas IL-5, IL-13 and IL-10 cytokine responses were positively associated with beta-cell function in adults and children. Essentially, the same results were obtained with three different models of regression analysis. CONCLUSIONS: The number of detectable islet-reactive immune cells decreases within 1-2 years after diagnosis of type 1 diabetes. Cytokine production by antigen-specific PBMC reactivity is related to beta-cell function as measured by stimulated C-peptide. Cellular immunity appears to regress soon after disease diagnosis and begin of insulin therapy.

High affinity binding of hydrophobic and autoantigenic regions of proinsulin to the 70 kDa chaperone DnaK.

BACKGROUND: Chaperones facilitate proper folding of peptides and bind to misfolded proteins as occurring during periods of cell stress. Complexes of peptides with chaperones induce peptide-directed immunity. Here we analyzed the interaction of (pre)proinsulin with the best characterized chaperone of the hsp70 family, bacterial DnaK. RESULTS: Of a set of overlapping 13-mer peptides of human preproinsulin high affinity binding to DnaK was found for the signal peptide and one further region in each proinsulin domain (A- and B-chain, C-peptide). Among the latter, peptides covering most of the B-chain region B11-23 exhibited strongest binding, which was in the range of known high-affinity DnaK ligands, dissociation equilibrium constant (K'd) of 2.2 ± 0.4 µM. The B-chain region B11-23 is located at the interface between two insulin molecules and not accessible in insulin oligomers. Indeed, native insulin oligomers showed very low DnaK affinity (K'd 67.8 ± 20.8 µM) whereas a proinsulin molecule modified to prevent oligomerization showed good binding affinity (K'd 11.3 ± 7.8 µM). CONCLUSIONS: Intact insulin only weakly interacts with the hsp70 chaperone DnaK whereas monomeric proinsulin and peptides from 3 distinct proinsulin regions show substantial chaperone binding. Strongest binding was seen for the B-chain peptide B 11-23. Interestingly, peptide B11-23 represents a dominant autoantigen in type 1 diabetes.

Health Effects of Coffee: Mechanism Unraveled?

The association of habitual coffee consumption with a lower risk of diseases, like type 2 diabetes mellitus, chronic liver disease, certain cancer types, or with reduced all-cause mortality, has been confirmed in prospective cohort studies in many regions of the world. The molecular mechanism is still unresolved. The radical-scavenging and anti-inflammatory activity of coffee constituents is too weak to account for such effects. We argue here that coffee as a plant food has similar beneficial properties to many vegetables and fruits. Recent studies have identified a health promoting mechanism common to coffee, vegetables and fruits, i.e., the activation of an adaptive cellular response characterized by the upregulation of proteins involved in cell protection, notably antioxidant, detoxifying and repair enzymes. Key to this response is the activation of the Nrf2 (Nuclear factor erythroid 2-related factor-2) system by phenolic phytochemicals, which induces the expression of cell defense genes. Coffee plays a dominant role in that regard because it is the major dietary source of phenolic acids and polyphenols in the developed world. A possible supportive action may be the modulation of the gut microbiota by non-digested prebiotic constituents of coffee, but the available data are still scarce. We conclude that coffee employs similar pathways of promoting health as assumed for other vegetables and fruits. Coffee beans may be viewed as healthy vegetable food and a main supplier of dietary phenolic phytochemicals.

Myocardial infarction and stroke in early years after diagnosis of type 2 diabetes: risk factors and relation to self-monitoring of blood glucose.

BACKGROUND: The natural course of macrovascular events in patients with type 2 diabetes was analyzed: what are the risk factors, and what is the relationship to the use of self-monitoring of blood glucose (SMBG)? METHODS: Data were retrieved from ROSSO-a German retrospective observational study-which followed 3,268 patients from diagnosis of type 2 diabetes for 6.5 +/- 1.6 years. We compared patients with or without a nonfatal macrovascular event (myocardial infarction or stroke) and patients using or not using SMBG. RESULTS: At baseline, worse glycemic control and higher body mass index were not risk factors for macrovascular events. Moreover, there was no association with classic risk factors like blood pressure or total cholesterol. Overall, there was a higher incidence of stroke than of myocardial infarction (0.78% vs. 0.51%). Myocardial infarction was positively associated with male sex, and stroke with age (P < 0.001 for each). Patients using SMBG compared to patients not using SMBG had fewer myocardial infarctions (2.0% vs. 4.0%, P = 0.002) and strokes (3.6% vs. 5.7%, P = 0.005), experienced a stroke later after diagnosis of type 2 diabetes (5.1 +/- 1.9 vs. 3.8 +/- 2.1 years, P < 0.001), and had a higher mean hemoglobin A1c in the years before a myocardial infarction (7.8 +/- 1.8% vs. 6.8 +/- 1.1%, P = 0.003) or a stroke (8.0 +/- 1.8% vs. 7.1 +/- 1.2%, P = 0.003). However, classic cardiovascular risk factors did not differ between patients using or not using SMBG. CONCLUSIONS: In patients with type 2 diabetes SMBG was associated with a lower event rate of myocardial infarction (-50%) and stroke (-37%), although at baseline the classic risk factors for macrovascular events were not different in both groups.

Deficient heat shock protein 70 response to stress in leukocytes at onset of type 1 diabetes.

Type 1 diabetes is caused by the immune-mediated destruction of pancreatic beta cells. Animal models of the disease demonstrate an increased susceptibility of beta cells to immunological attacks due to their defective stress-responsiveness. To investigate the stress-responsiveness in human type 1 diabetes we analyzed the heat-inducibility of the dominant stress protein heat shock protein (Hsp)70 in diabetic patients at different disease stages. At diabetes-manifestation heat-induced Hsp70 levels in peripheral blood mononuclear cells (PBMC) reached only about 25% of the levels expressed by heat-treated PBMC from non-diabetic subjects (p<0.05). Heat-responsiveness improved with disease duration and was re-established at more than eight months after disease-manifestation. Hyperthermia-induced Hsp70 expression was decreased by the T-helper 1-associated cytokine interferon-gamma and increased by the T-helper 2-associated transforming growth factor-beta. We conclude that impaired cellular stress-responsiveness, aggravated by the inflammatory milieu at the onset of type 1 diabetes, contributes to disease manifestation.

[Non-pharmacological diabetes therapy]. / Nichtpharmakologische Diabetestherapie.

Diabetes mellitus type 2 is a life-style disease that is triggered by obesity and lack of physical activity. The pathophysiological basis of the disease is a reduction of insulin sensitivity, that is caused by the trigger factors. Glucose metabolic disorders appear if overproduction of insulin can not compensate the insulin resistance. In early phases postprandial blood glucose is increased, in late phases elevation of fasting blood glucose is noted. In the general awareness manifestation of type 2 diabetes is associated with an initiation of a pharmacological therapy. This is not the case, as described in detail in this review. Next to epidemiological studies, which indicate trigger factors, intervention trials will be discussed that led to a shift in paradigm in the diabetology. Non-pharmacological interventions are a therapeutical alternative in a lot of patients or are able to reduce the amount of antidiabetic agents significantly.