We concluded that low dosage GLP-1 improves the ability of the beta-cell to secrete insulin in both IGT and NIDDM subjects, but that the ability to sense and respond to subtle changes in plasma glucose is improved in IGT subjects, with only a variable response in NIDDM subjects. Beta-cell dysfunction was improved by GLP-1 infusion, suggesting that early GLP-1 therapy may preserve beta-cell function in subjects with IGT or mild NIDDM.
only abstract available here. Mouse model finds possible explanation for low Testosterone and diabetes link. Actually, the link is between the metabolite DHT and the AR. The activity of AR from DHT binding induces beta cell insulin secretion in the presence of glucose. This is dependent on glucagon-like peptide 1 receptor activation also, which AR activation by DHT does in fact do.
Increased resistance to insulin action in the skeletal muscle and liver associated with enhanced hepatic glucose
output and impaired insulin secretion due to a progressive decline of β-cell function are long-recognized core defects
in addition, other mechanisms/organs are involved, augmenting the pathological pathways: adipocytes (altered fat metabolism
due to insulin resistance), gastrointestinal tract (incretin deficiency and/or resistance), pancreatic α-cells (hyperglucagonemia
and increased hepatic sensitivity to glucagon), kidneys (enhanced glucose reabsorption), and central nervous system (insulin
resistance)
Incretins are gut-derived hormones, members of the glucagon superfamily, released in response to nutrient ingestion (mainly
glucose and fat)
They exert a wide range of effects, including stimulation of pancreatic insulin secretion in a glucose-dependent
manner and play an important role in the local gastrointestinal and whole-body physiology
it is clear that serum IGF-1 and or IGFBP-3 can be normal in patients with undisputed GHD
Various investigators have reported normal IGF-1 values in 37–70% of GH deficient adults
The co-administration of arginine and GHRH (the combined test) is a powerful stimulus for GH production and has gained increasing acceptance as a useful method of diagnosing GHD [34]. This test has been advocated as a suitable alternative to ITT
The glucagon stimulation test (GST) is a reliable, safe alternative to the ITT in the diagnosis of GHD
An intravenous infusion of arginine (0.5 g/kg body weight) together with an intravenous bolus of GHRH (1 mcg/kg body weight) is administered [30]. Serum samples for GH are then obtained every 15–30 minutes for two hours.
Obesity, particularly marked obesity, is associated with blunted GH secretion in response to provocative stimuli
It has also been suggested that that even mildly increased BMI (25–30 kg/m2) can result in diminished stimulated GH production in 13% of healthy subjects
Corneli et al. have defined BMI-specific cut-off points for diagnosing adult-onset GHD using GHRH + arginine—11.5 ng/mL for those with BMI < 25 kg/m2, 8.0 ng/mL for BMI 25–30 kg/m2, 4.2 ng/mL for those with BMI > 30 kg/m2
GH levels are higher during the luteal phase in comparison with the follicular phase of the cycle
Oral, in contrast to transdermal oestrogen, lowers IGF-1 levels and is associated with increased GH levels
Adequate pituitary replacement with thyroxine and hydrocortisone are needed for optimal GH production
one cannot rely on a low IGF-1 to diagnose GHD in women taking oral oestrogen preparations.
Numerous GH secretagogues are available with the insulin tolerance test being the gold standard and the glucagon stimulation test or the GHRH + arginine as acceptable alternatives
ain et al. found the GST to be at least as good as the ITT in provoking GH secretion
the GST is safe, with almost no contraindications, it causes nausea and sometimes vomiting in 15–20% of subjects
Study finds 50 mg of DHEA improves insulin sensitivity in Hypoadrenal women. The authors also found and increase in DHEAS, bioavailable T, androstenedione, and a reduced SHBG, insulin, and glucagon.
Exercise is not just for calories out. Exercise increases growth hormone, IGF-1, glucagon-like peptide 1, IL-6, and IL-1ra. The effect is to GH increases beta islet cell mass and protects beta cell lines against IL-1beta, Interferon-gamma and TNF-alhpa induced apoptosis. IL-6 increased production increases GLP-1 and IL-1ra which counters IL-1beta. Interleukin-1beta induces islet cell apoptosis and thus IL-1ra counters this pro-inflammatory signal.
The incretins are peptide hormones released from the small intestine during meal absorption that stimulate insulin secretion
from pancreatic β-cells and reduce excessive secretion of glucagon by pancreatic α-cells
Five branched chain and aromatic amino acids (isoleucine, leucine, valine, tyrosine, and phenylalanine) showed significant associations with future diabetes
there is increasing evidence that longer term high-protein intake may have detrimental effects on insulin resistance [68, 117–123], diabetes risk [69], and the risk of developing cardiovascular disease
high-protein and the high GI diets significantly increased markers of low-grade inflammation
significant and clinically relevant worsening of insulin sensitivity with an isoenergetic plant-based high-protein diet
healthy humans that are exposed to amino acid infusions rapidly develop insulin resistance
longer term high-protein intake has been shown to result in whole-body insulin resistance [68, 118], associated with upregulation of factors involved in the mammalian target of rapamycin (mTOR)/S6K1 signalling pathway [68], increased stimulation of glucagon and insulin within the endocrine pancreas, high glycogen turnover [118] and stimulation of gluconeogenesis [68, 118].
it was recently shown in a large prospective cohort with 10 years followup that consuming 5% of energy from both animal and total protein at the expense of carbohydrates or fat increases diabetes risk by as much as 30% [69]. This reinforces the theory that high-protein diets can have adverse effects on glucose metabolism.
Another recent study showed that low-carbohydrate high-protein diets, used on a regular basis and without consideration of the nature of carbohydrates or the source of proteins, are also associated with increased risk of cardiovascular disease [70], thereby indicating a potential link between high-protein Western diets, T2DM, and cardiovascular risk.
The starting point for innate immunity activation is the recognition of conserved structures of bacteria, viruses, and fungal
components through pattern-recognition receptors
TLRs are PRRs that recognize microbe-associated molecular patterns
TLRs are transmembrane proteins containing extracellular domains rich in leucine repeat sequences and a cytosolic domain
homologous to the IL1 receptor intracellular domain
The major proinflammatory mediators produced by the TLR4 activation in response to endotoxin (LPS) are TNFα, IL1β and IL6,
which are also elevated in obese and insulin-resistant patients
Obesity,
high-fat diet, diabetes, and NAFLD are associated with higher gut permeability leading to metabolic endotoxemia.
Probiotics,
prebiotics, and antibiotic treatment can reduce LPS absorption
LPS promotes hepatic insulin
resistance, hypertriglyceridemia, hepatic triglyceride accumulation, and secretion of pro-inflammatory cytokines promoting
the progression of fatty liver disease.
In the endothelium, LPS induces the expression of pro-inflammatory, chemotactic, and
adhesion molecules, which promotes atherosclerosis development and progression.
In the adipose tissue, LPS induces adipogenesis,
insulin resistance, macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines and chemokines.
the gut microbiota has been recently proposed to be an environmental factor involved
in the control of body weight and energy homeostasis by modulating plasma LPS levels
dietary fats alone might not be sufficient to cause overweight and obesity, suggesting that a
bacterially related factor might be responsible for high-fat diet-induced obesity.
This was accompanied in high-fat-fed mice by a change in gut microbiota composition, with reduction in
Bifidobacterium and Eubacterium spp.
n humans, it was also shown that meals with high-fat and high-carbohydrate content (fast-food style western diet) were able
to decrease bifidobacteria levels and increase intestinal permeability and LPS concentrations
it was demonstrated that, more than the fat amount, its composition was a critical modulator of ME (Laugerette et al. 2012). Very recently, Mani et al. (2013) demonstrated that LPS concentration was increased by a meal rich in saturated fatty acids (SFA), while decreased after a
meal rich in n-3 polyunsaturated fatty acids (n-3 PUFA).
this effect seems to be due to the fact that some SFA (e.g., lauric and mystiric acids) are part of the lipid-A component
of LPS and also to n-3 PUFA's role on reducing LPS potency when substituting SFA in lipid-A
these experimental results suggest a pivotal role of CD14-mediated TLR4 activation in the development of
LPS-mediated nutritional changes.
This suggests a link between gut microbiota, western diet, and obesity and indicates that gut microbiota manipulation can
beneficially affect the host's weight and adiposity.
endotoxemia was independently
associated with energy intake but not fat intake in a multivariate analysis
in vitro that endotoxemia activates pro-inflammatory cytokine/chemokine production via NFκB and MAPK signaling in preadipocytes and
decreased peroxisome proliferator-activated receptor γ activity and insulin responsiveness in adipocytes.
T2DM patients have mean values of LPS that are 76% higher than healthy controls
LPS-induced release of glucagon, GH and cortisol, which inhibit glucose uptake, both
peripheral and hepatic
LPSs also seem to induce ROS-mediated apoptosis in pancreatic cells
Recent evidence has been linking ME with dyslipidemia, increased intrahepatic triglycerides, development, and progression
of alcoholic and nonalcoholic fatty liver disease
The hepatocytes, rather than hepatic macrophages, are the cells responsible for its clearance, being ultimately excreted
in bile
All the subclasses of plasma lipoproteins can bind and neutralize the toxic effects of LPS, both in vitro (Eichbaum et al. 1991) and in vivo (Harris et al. 1990), and this phenomenon seems to be dependent on the number of phospholipids in the lipoprotein surface (Levels et al. 2001). LDL seems to be involved in LPS clearance, but this antiatherogenic effect is outweighed by its proatherogenic features
LPS produces hypertriglyceridemia by several mechanisms, depending on LPS concentration. In animal models, low-dose LPS increases
hepatic lipoprotein (such as VLDL) synthesis, whereas high-dose LPS decreases lipoprotein catabolism
When a dose of LPS similar to that observed in ME was infused in humans, a 2.5-fold increase in endothelial lipase was observed,
with consequent reduction in total and HDL. This mechanism may explain low HDL levels in ‘ME’ and other inflammatory conditions
such as obesity and metabolic syndrome
It is known that the high-fat diet and the ‘ME’ increase intrahepatic triglyceride accumulation, thus synergistically contributing
to the development and progression of alcoholic and NAFLD, from the initial stages characterized by intrahepatic triglyceride
accumulation up to chronic inflammation (nonalcoholic steatohepatitis), fibrosis, and cirrhosis
On the other hand, LPS activates Kupffer cells leading to an increased production of ROS and pro-inflammatory cytokines
like TNFα
high-fat diet mice presented with ME, which
positively and significantly correlated with plasminogen activator inhibitor (PAI-1), IL1, TNFα, STAMP2, NADPHox, MCP-1, and
F4/80 (a specific marker of mature macrophages) mRNAs
prebiotic administration reduces intestinal permeability
to LPS in obese mice and is associated with decreased systemic inflammation when compared with controls
Cani et al. also found that high-fat diet mice presented with not only ME but also higher levels of inflammatory markers, oxidative
stress, and macrophage infiltration markers
This suggests that important links between gut microbiota, ME, inflammation, and oxidative stress are implicated in a high-fat
diet situation
high-fat feeding is associated with adipose
tissue macrophage infiltration (F4/80-positive cells) and increased levels of chemokine MCP-1, suggesting a strong link between
ME, proinflammatory status, oxidative stress, and, lately, increased CV risk
LPS has been shown to promote atherosclerosis
markers of systemic inflammation such as circulating bacterial endotoxin
were elevated in patients with chronic infections and were strong predictors of increased atherosclerotic risk
As a TLR4 ligand, LPS has been suggested to induce atherosclerosis development and progression, via a TLR4-mediated inflammatory
state.
The gut microbial composition is altered during pregnancy
probiotic supplements may contribute to the maintenance of bacterial diversity and glucose homeostasis in individuals with metabolic disturbances
Assessment of four randomized controlled trials in this review involving 288 pregnant women with GDM found that a 6–8 week probiotic intervention did not improve FBG or LDL-cholesterol levels
probiotic supplementation in women with GDM was associated with significant reductions in insulin resistance
One proposed method is by the production of short chain fatty acids (SCFAs), generated as a by-product of bacterial fermentation of dietary fibers. SCFAs act as an energy source for intestinal cells and have been found to regulate the production of hormones effecting energy intake and expenditure such as leptin and grehlin
Another hypothesized mechanism of SCFA action includes reducing gastrointestinal permeability by upregulating transcription of tight junction proteins, enhancing production of Glucagon-like peptide-2 (GLP-2) which promotes crypt cell proliferation, and reducing inflammation in colonic epithelial cells by increasing PPAR-gamma activation
Maintenance of the integrity of the gut barrier minimizes the concentration of lipopolysaccharide (LPS) in circulation
LPS is a structural component of gram negative bacterial cell walls, which induces an immune-cell response upon absorption into the human bloodstream, stimulating proinflammatory cytokine production and the onset of insulin resistance and hyperglycemia
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