Diabetes Mellitus, Type 2
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Pubmed
Journal: Diabetes care
December/20/2005
Pubmed
Journal: Journal of diabetes science and technology
January/15/2014
Abstract
BACKGROUND
Increased glycemic variability is associated with an increase risk of adverse clinical outcomes in diabetes. Central to the understanding of diabetes is glucose homeostasis. "Good" homeostasis is equated to low glycemic variability, and "poor" homeostasis is linked to greater glycemic variability. We have, therefore, developed a method with the aim to objectively quantify the domain of glucose-insulin homeostasis. We have termed this method as Observed Variability And Lability (OVAL).
METHODS
Blood samples for the measurement of glucose and insulin concentrations were acquired every 2 min for 120 min from 12 patients with type 2 diabetes mellitus [T2DM; median (range) age 35 (25-47) years and duration of diabetes 7 (2-9) years receiving oral hypoglycemic treatment] and 27 controls [aged 38(30-53) years] with an equal split of genders and equal distribution of body mass indexes. The insulin-glucose time variant data form the boundaries of OVAL, defined as the ellipse enclosing the 95% confidence intervals of the insulin and glucose concentrations plotted on an x-y scatter graph and normalized to ensure equal weighting of insulin and glucose.
RESULTS
Less precise OVAL homeostasis was observed in subjects with T2DM, by a factor of 4, in comparison with controls [OVAL, T2DM 7.8(3.8) versus controls 1.9(1.0); p = .0003]. The assessment remained statistically robust (p < .001) with increased sampling intervals up to 8 min.
CONCLUSIONS
The OVAL model is a robust method for measuring glucose-insulin homeostasis in controls and T2DM subjects (available online at http://www.oval-calc.co.uk). Deranged glucose-insulin homeostasis is the hallmark of diabetes and OVAL has the capacity to quantify in the fasting state.
Pubmed
Journal: Kidney international
November/21/2010
Abstract
Most mouse models of diabetes do not fully reproduce features of human diabetic nephropathy, limiting their utility in inferring mechanisms of human disease. Here we performed detailed phenotypic and genetic characterization of leptin-receptor (Lepr) deficient mice on the FVB/NJ background (FVB(db/db)), an obese model of type II diabetes, to determine their suitability to model human diabetic nephropathy. These mice have sustained hyperglycemia, significant albuminuria and characteristic diabetic renal findings including mesangial sclerosis and nodular glomerulosclerosis after 6 months of age. In contrast, equally obese, hyperglycemic Lepr/Sur1 deficient C57BL/6J (Sur1 has defective insulin secretion) mice have minimal evidence of nephropathy. A genome-wide scan in 165 Lepr deficient backcross progeny derived from FVB/NJ and C57BL/6J identified a major locus influencing nephropathy and albuminuria on chromosome 8B1-C5 (Dbnph1 locus, peak lod score 5.0). This locus was distinct from those contrasting susceptibility to beta cell hypertrophy and HIV-nephropathy between the same parental strains, indicating specificity to diabetic kidney disease. Genome-wide expression profiling showed that high and low risk Dbnph1 genotypes were associated with significant enrichment for oxidative phosphorylation and lipid clearance, respectively; molecular pathways shared with human diabetic nephropathy. Hence, we found that the FVB(db/db) mouse recapitulates many clinical, histopathological and molecular features of human diabetic nephropathy. Identifying underlying susceptibility gene(s) and downstream dysregulated pathways in these mice may provide insight into the disease pathogenesis in humans.
Pubmed
Journal: Diabetes care
June/25/1997
Abstract
OBJECTIVE
To examine prospectively the association between modern oral contraceptives with low doses of estrogen and progestin and subsequent incidence of NIDDM.
METHODS
In a prospective cohort study, 98,590 U.S. female nurses aged 25 to 42 and free of diagnosed diabetes, coronary heart disease, stroke, and cancer at baseline in 1989 were followed for 4 years. Endpoint was incidence of confirmed NIDDM. Oral contraceptive use was reported on mailed questionnaires.
RESULTS
During 352,067 person-years follow-up, we confirmed 185 incident cases of NIDDM. After adjusting for age, BMI, cigarette smoking, family history of diabetes, parity, physical activity, alcohol intake, ethnicity, history of diagnosis of infertility, elevated cholesterol, and hypertension, women currently using oral contraceptives had a relative risk (RR) of 1.6 (95% CI, 0.9-3.1). For past users, the multivariate RR was 1.2 (95% CI, 0.8-1.8). This association was attenuated after restricting the analysis to symptomatic cases of NIDDM. For current users, RR = 1.3 (95% CI, 0.6-2.8), and for past users, RR = 0.9 (95% CI, 0.6-1.4), suggesting that increased surveillance may explain at least part of any excess risk.
CONCLUSIONS
In this large prospective study, we found no appreciable increase in the 4-year risk of NIDDM among current users of oral contraceptives. There was no apparent increase in risk among past users. The small number of cases reflect the low absolute risk of NIDDM in this population of young women.
Pubmed
Journal: Diabetes, obesity & metabolism
April/11/2011
Abstract
Islet protein profiling is defined as generation of extended protein expression data sets from islets or islet cells. Islets from rodent control and animal models of type 1 and type 2 diabetes mellitus and healthy humans and insulin- and glucagon-producing cell lines have been used. Protein profiling entails separation, differential expression determination, identification and expression analysis. Protein/peptide separation is either gel-based or by chromatography. Differential expression is based on comparison of visualized spots/proteins between gels or by sample labelling in gel-free systems. Identification of proteins is made by tryptic fragmentation of proteins, fragment mass determination and mass comparison with protein databases. Analysis of expression data sets interprets the complex protein changes into cellular mechanisms to generate hypotheses. The importance of such protein expression sets to elucidate islet cellular events is evidenced by the observation that only about 50% of the differentially expressed proteins and transcripts showed concordance when measured in parallel. Using protein profiling, different areas related to islet dysfunction in type 1 and type 2 diabetes mellitus have been addressed, including dysfunction induced by elevated levels of glucose and fatty acids and cytokines. Because islets from individuals with type 1 or type 2 diabetes mellitus have not yet been protein profiled, islets from rat (BB-DP) and mouse (NOD, ob/ob, MKR) models of the disease have been used, and mechanisms responsible for islet dysfunction delineated offering avenues of intervention.
Authors
Pubmed
Journal: Journal of medicinal chemistry
July/16/2012
Abstract
As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2',6'-dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4'-position. Further optimization of this position and the linker led to the discovery of several 4'-alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4-[({4'-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoic acid (35) exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.
Pubmed
Journal: Endocrine
August/18/2005
Abstract
The age-related changes in acute insulin response after glucose loading and the influence of suppression of body weight gain were investigated by using blood samples from portal and peripheral veins. We placed indwelling catheters in the portal vein of 12- and 24- wk-old Otsuka Long-Evans Tokushima fatty (OLETF) rats (n = 8, 12), and age-matched control Long-Evans Tokushima Otsuka (LETO) rats (n = 8, 6). To suppress the body weight gain, 6 out of 12 OLETF rats were fed chow containing 50 ppm voglibose (VOG) from 8 until 24 wk of age. After fasting for 17 h, rats underwent 1 g/kg oral glucose tolerance test (OGTT). Peripheral glucose levels after glucose loading were significantly higher in 12- and 24-wk-old OLETF rats than in the age-matched LETO rats. Values for delta insulin 15 min/delta glucose 15 min (delta I15 min/delta G15 min) in portal blood were 0.029 +/- 0.011 and 0.009 +/- 0.009 (12 wk of age) and 0.03 +/- 0.03 and -0.01 +/- 0.01 (24 wk of age) in the LETO rats and OLETF rats. At the age of 24 wk, the body weights in VOG-treated OLETF rats were significantly lower than those in the OLETF rats. And there was significantly greater acute insulin response to glucose in VOG-treated OLETF rats than in the OLETF rats. Acute insulin response to glucose decreased with advancing age and the suppression of body weight gain preserved the response in spontaneously type 2 diabetic rats with visceral fat obesity.
Pubmed
Journal: Expert review of cardiovascular therapy
May/3/2006
Abstract
The metabolic syndrome is a clustering of risk factors known to promote or increase the risk for development of cardiovascular disease. Recent estimates demonstrate that approximately one-third of the adult population of developed countries are characterized with metabolic syndrome by different definitions. Metabolic syndrome, even in the absence of diabetes, is associated with an increased risk of cardiovascular disease and total mortality, as well as an increased risk for the development of diabetes. Patients with diabetes are considered a cardiovascular risk equivalent, and warrant aggressive management of underlying risk factors to optimize prevention of cardiovascular disease. Initial evaluation of coronary heart disease risk involves global risk estimation using Framingham or other algorithms for risk prediction. Furthermore, consideration of screening for novel risk factors, such as C-reactive protein, as well as subclinical atherosclerosis (as assessed by carotid ultrasound, computed tomography or ankle-brachial index), can further refine the estimation of future cardiovascular disease risk. The presence of subclinical atherosclerosis or elevated levels of C-reactive protein can potentially modify recommended treatment goals for lipid and other cardiovascular risk factors.
Pubmed
Journal: Medizinische Klinik (Munich, Germany : 1983)
September/13/1998
Abstract
BACKGROUND
The neuroglycopenic syndrome, which is often due to sulfonylurea-induced hypoglycemia, is frequently overlooked or misinterpretated as cerebral ischemia.
METHODS
Two women aged 81 and 83 years, respectively, with type II diabetes treated with sulfonylureas presented with hemiparesis, dysphasia and somnolence. Both, general practitioner and emergency room physician first interpretated the symptoms as clinical signs of stroke without determination of blood glucose. After hours of delay due to unnecessary and expensive examinations including cerebral computed tomography the correct diagnosis of hypoglycemia was finally made. After injection of i.v. glucose the symptomatology was completely reversible.
CONCLUSIONS
In every case of disturbance of consciousness, acute neurologic deficits and psychiatric abnormalities an immediate blood glucose test should be performed to exclude hypoglycemia.
Pubmed
Journal: Annals of the New York Academy of Sciences
July/11/2002
Abstract
Different autoimmune mechanisms may be involved in childhood- and adult-onset type 1 diabetes. Our aim was to explore the differences in IA-2 autoantibody epitope recognition between childhood- and adult-onset type 1 diabetes. Therefore, in vitro synthesized radiolabeled IA-2ic (amino acid 601-979), IA-2JM (amino acid 557-629), and IA-2PTP (amino acid 630-979) were used to analyze the IA-2 autoantibody epitope specificities in 93 patients with new-onset type 1 diabetes. Among 93 patients with type 1 diabetes the prevalences of autoantibodies to GAD, IA-2ic, and insulin were 69.9%, 58.1%, and 45.2%, respectively. The prevalence of IA-2ic autoantibodies in patients with childhood-onset type 1 diabetes (aged <or=18 years, n = 60) was significantly higher than that in patients with adult-onset diabetes (68.3 vs. 36.4%, P < 0.002). Ninety-two percent of type 1 diabetic patients positive for IA-2ic autoantibodies recognized the PTP domain of IA-2, whereas 8% reacted with the JM region only. Among 60 patients with childhood-onset type 1 diabetes, 2% recognized the JM region only, 48% bound the PTP domain of IA-2 only, and 18% recognized both JM and PTP epitopes. Among 33 patients with adult-onset diabetes, 9% recognized the IA-2JM only, 18% bound the IA-2PTP only, and 9% recognized both the IA-2JM and the IA-2PTP. IA-2PTP autoantibodies were prevalent in patients with childhood-onset type 1 diabetes. By contrast, the proportion of patients with the IA-2JM autoantibody only in type 1 diabetes who were positive for IA-2ic autoantibodies was significantly higher in adult-onset than in childhood-onset diabetes (P < 0.05). These results demonstrate that autoantibody recognition of the IA-2 epitope is distinct in childhood-onset and adult-onset type 1 diabetes.
Pubmed
Journal: Annals of the New York Academy of Sciences
July/11/2002
Abstract
Insulin-dependent diabetes mellitus (IDDM) is a polygenic disorder with an autoimmune basis for disease development. In addition to HLA, a second susceptibility locus for IDDM has been identified to lie in the major histocompatibility class III region. MIC-A is located in the MHC class III region and is expressed by monocytes, keratinocytes, and endothelial cells. Sequence determination of the MIC-A gene identifies trinucleotide repeat (GCT) microsatellite polymorphism in exon 5. Five alleles with 4, 5, 6, and 9 repetitions of GCT or 5 repetitions of GCT with 1 additional nucleotide insertion (GGCT) are identified. The alleles are A4, A5, A5.1, A6, and A9. The aim of our study was to find the association of MIC-A alleles with IDDM, malnutrition-modulated diabetes mellitus (MMDM), and non-insulin-dependent diabetes mellitus (NIDDM) patients. IDDM (n = 52), MMDM (n = 41), NIDDM (n = 212), and healthy controls (n = 73) from Cuttack, in eastern India, were studied. Of the 212 NIDDM patients analyzed, 96 of them were found to be positive for either GAD65 or IA-2 antibodies. Autoantibodies to GAD65 and IA-2 were measured by radioligand binding assay using (35)S-labeled recombinant human GAD65 and IA-2 in an in vitro transcription/translation system. Autoantibody-positive NIDDM patients (n = 96) and adult healthy controls for NIDDM (n = 113) were also compared. These autoantibody-positive NIDDM patients are considered as slow-onset IDDM or latent autoimmune diabetes in adults (LADA) patients. The samples were analyzed for MIC-A by PCR amplification, and fragment sizes were determined in an ABI prism DNA sequencer. The results of the MIC-A typing are: allele 9 of MIC-A is positively associated (OR 3.62; P < 0.001), and allele 4 is negatively associated (OR 0.31; P < 0.05) with MMDM patients compared to controls. Allele 5 is positively associated with IDDM (OR 2.64; P < 0.05) when compared to controls. Allele 5.1 is positively associated in the autoantibody-positive NIDDM patients compared to adult controls. Our findings of a significant increase of allele A9 in MMDM patients compared to healthy controls suggest that MMDM is immunogenetically different from IDDM in eastern India. MIC-A is important in the pathogenesis of MMDM patients from Cuttack. MIC-A alleles distinguish acute-onset IDDM from slow-onset IDDM, indicating that this molecule may be important for delaying the onset of IDDM with the result that these patients are diagnosed clinically as NIDDM.
Pubmed
Journal: Current diabetes reports
April/3/2003
Abstract
Diabetes is a common complication of cystic fibrosis (CF), occurring in approximately 40% of adult patients. It is clinically distinct from type 1 or type 2 diabetes, and requires a unique approach. Because of evidence that it is associated with increased morbidity and mortality, prompt diagnosis and aggressive management of CF-related diabetes (CFRD) is important. The Cystic Fibrosis Foundation held a consensus conference in 1998 to define the current standards for the diagnosis and care of this disease. This article reviews those recommendations, and presents a practical approach to the management of CFRD.
Pubmed
Journal: American journal of kidney diseases : the official journal of the National Kidney Foundation
January/27/1998
Abstract
Fluid retention develops relatively early in the renal insufficiency of patients with diabetic nephropathy. The objective of this study was to clarify the effect of postural change on urine volume and urinary sodium excretion in diabetic nephropathy. Subjects consisted of 16 patients with non-insulin-dependent diabetes mellitus (five with diabetic nephrotic syndrome [DNS], five with nonnephrotic overt diabetic nephropathy [NNODN], and six without overt diabetic nephropathy [ODN]) and 11 patients with nondiabetic renal diseases (five with nondiabetic nephrotic syndrome [NDNS] and six without nephrotic syndrome). Patients were studied during 60 minutes of recumbency, followed by 60 minutes of standing. Mean blood pressure decreased in the standing posture only in patients with DNS and nondiabetic renal diseases. Urine volume decreased in the standing posture in the three groups of diabetic patients. Urine volume showed no changes in the standing posture in nondiabetic patients with and without nephrotic syndrome. The decreases in mean blood pressure and urine volume and the percentage decrease in creatinine clearance were significantly larger in patients with DNS than in those with NDNS and NNODN. The increase in free water clearance was significantly smaller in patients with DNS than in those with NDNS and NNODN. Urinary sodium excretion decreased in the standing posture in diabetic and nondiabetic patients, while no differences in the magnitude of changes were noted among patients with NDNS, NNODN, and DNS. It is concluded that the standing posture causes a greater decrease in urine volume due to orthostatic hypotension in patients with DNS compared with those with NDNS and NNODN, and that the presence of orthostatic hypotension in patients with DNS is likely responsible for the greater fluid retention of this group compared with other nephrotic patients with similar degrees of hypoalbuminemia.
Pubmed
Journal: Diabetes & metabolism
August/15/2001
Abstract
Epidemiological surveys show a large variation of type 2 diabetes (DT2) prevalence from one country to another, suggesting ethnic discrepancies in insulin sensitivity. Many data seem to confirm this hypothesis. We will show them while concentrating on data provided by surveys performed in French-speaking countries. The mechanisms of the ethnic differences in insulin sensitivity are unclear and further insights are needed. More than genetic factors, environmental factors appear to be involved in the occurence of insulin resistance and DT2. The epidemic nature of obesity and subsequent DT2 in the world urges health authorities in each country to raise campaigns to promote changes in life style and nutritional habits before the announced pandemy of DT2 becomes reality.
Pubmed
Journal: American journal of human biology : the official journal of the Human Biology Council
January/11/2006
Abstract
Pacific Islands populations can be broadly divided into Austronesians (AN) and Non-Austronesians (NAN); obesity and type 2 diabetes are prevalent in the former, although leptin levels in both groups have seldom been investigated. Thirty-seven (20 male and 17 female) adult pairs, matched by age and percent body fat, from AN-speaking Balopa and NAN-speaking Huli, all of whom migrated to settle in Port Moresby, the capital of Papua New Guinea, were selected for comparison of their serum leptin concentrations. The Balopa did not differ significantly from the Huli in age (30.5 +/- 9.7 and 30.0 +/- 8.7 years for males, 33.7 +/- 8.9 and 34.1 +/- 7.5 years for females, respectively) or percent body fat (19.4 +/- 5.6 and 18.8 +/- 4.6 for males, 34.1 +/- 6.2 and 33.3 +/- 5.0 for females), although the BMI of females was lower in the Balopa (26.4 +/- 4.9) than in the Huli (29.7 +/- 4.7) (P = 0.02). In both ethnic groups, females had markedly higher leptin concentrations than males, but there was no significant inter-group difference in males (3.5 +/- 2.6 and 3.1 +/- 4.7 ng/ml, P = 0.14) or females (22.7 +/- 12.9 and 19.7 +/- 11.9 ng/ml, P = 0.40), after controlling for lifestyle factors and serum lipids. Multiple regression analysis revealed that significant predictors of leptin concentration were % body fat (beta = 0.58), sex (male, 0; female, 1; beta = 0.27), and smoker status (non-smoker, 0; smoker, 1; beta = -0.15) (R(2) = 0.80), implying that the leptin concentration was primarily determined by lifestyle-derived body fatness. In conclusion, the NAN populations do not endogenously differ in leptin status from the AN populations, who have been recognized as a typical group with a "thrifty" genotype.
Pubmed
Journal: Diabetes care
September/11/1988
Abstract
We have specifically examined warm and cool sensitivities in 60 diabetic and 43 nondiabetic individuals. Diabetic patients tended to have less warm and cool sensitivity than the control subjects (P less than .001 for age less than 50 yr and P less than .05 for age greater than or equal to 50 yr). Both patients asymptomatic for neuropathy and patients with symptoms had impairment of warm and cool sensitivity (P less than .05 for comparisons with control subjects). These differences persisted (P less than .05) in covariance analyses with age included as a covariate. There was a nonlinear association between warm sensitivity and hemoglobin A1c. Warm-sensitivity values in the lowest and middle tertiles of the hemoglobin A1c distribution were similar; however, warm-sensitivity values of patients in the highest tertile were markedly increased (P less than .05 for the comparison of the highest tertile with the lowest and middle tertiles combined). There tended to be more warm insensitivity than cool insensitivity among the diabetic patients, and this difference increased with worsening glycemia. These data indicate that both warm and cool sensations are markedly impaired in asymptomatic adult diabetic patients. They also suggest that warm sensitivity is more impaired than cool sensitivity, and that this is the result of a stronger association between warm sensitivity and metabolic factors.
Pubmed
Journal: The American journal of the medical sciences
March/27/2006
Abstract
Metformin-associated lactic acidosis (MALA) is a rare but serious clinical entity. It is almost always seen in patients with a serious underlying medical disorder, most often a degree of renal impairment or other factors that are known to predispose to the lactic acidosis. We report a case of MALA in which acute renal failure resulting from hypovolemia secondary to acute gastroenteritis likely precipitated the condition. Early recognition of this condition and initiation of treatment are important. Bicarbonate hemodialysis is the treatment of choice.
Pubmed
Journal: Current hypertension reports
May/7/2003
Abstract
The renin-angiotensin system plays a key role in the progression of kidney disease, in addition to its well-described role in the maintenance of extracellular fluid volume and blood pressure. Recent studies have shown that blockade of the renin-angiotensin system at the level of the angiotensin II type 1 receptor can have important effects on proteinuria and the rate of progression of kidney disease in patients with type 2 diabetes mellitus. This review first discusses recent experimental studies relating angiotensin II to kidney function in diabetes mellitus and changes in glomerular permselectivity, and then focuses on recent clinical trials with angiotensin II receptor blockers in patients with type 2 diabetes mellitus.
Pubmed
Journal: Endocrine journal
November/3/2014
Abstract
To examine how elevated alanine aminotransferase (ALT) could be associated with newly diagnosed diabetes mellitus. We conducted a cross-sectional analysis on a mass health examination. The odds ratios (ORs) for diabetes mellitus and newly diagnosed diabetes mellitus were compared between people with and without abdominal obesity, together with and without elevated ALT levels. 5499 people were included in this study. Two hundred fifty two (4.6%) fulfilled the diagnosis of diabetes mellitus with 178 (3.2%) undiagnosed before. Metabolic syndrome was vigorously associated with diabetes mellitus and newly diagnosed diabetes mellitus (12.4% vs. 1.4% and 9.0% vs. 0.9%), but elevated ALT alone was not. However, coexisting with obesity, elevated ALTs were robustly associated with diabetes mellitus and newly diagnosed diabetes mellitus. For the incidence of newly diagnosed diabetes mellitus, in comparison to non-obese people with normal ALT (1.7%, OR = 1), obese people especially with elevated ALT levels had significantly higher ORs (obese with ALT ≤ 40 U/L: 4.7%, OR 1.73, 95% CI 1.08-2.77, P 0.023; ALT 41-80 U/L: 6.8%, OR 2.06, 95% CI 1.20-3.55, P 0.009; ALT 81-120 U/L: 8.8%, OR 3.07, 95% CI 1.38-6.84, P 0.006; ALT > 120 U/L: 18.2%, OR 7.44, 95% CI 3.04-18.18, P < 0.001). Abdominal obesity validates the association between elevated alanine aminotransferase and diabetes mellitus and newly diagnosed diabetes mellitus. People with abdominal obesity, especially with coexisting elevated ALT levels should be screened for undiagnosed diabetes mellitus.
Pubmed
Journal: Acta diabetologica
April/19/2015
Abstract
Occasional cases of bilateral, symmetrical, seronegative polyarthritis have been reported in patients treated with dipeptidyl peptidase-4 inhibitors (Crickx et al. in Rheumatol Int, 2013). We report here a similar case observed during treatment with a GLP-1 receptor agonist. A 42-year-old man with type 2 diabetes treated with metformin 1,500 mg/day and liraglutide 1.8 mg/day. After 6 months from the beginning of treatment, the patient complained of bilateral arthralgia (hands, feet, ankles, knees, and hips). Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and leukocytes were increased. Rheumatoid factor, anticyclic citrullinated protein antibody, antinuclear antibodies, anti-Borrelia, and burgdorferi antibodies were all negative, and myoglobin and calcitonin were normal. Liraglutide was withdrawn, and the symptoms completely disappeared within 1 week, with normalization of ESR, CRP, fibrinogen, and leukocytes. Previously described cases of polyarthritis associated with DPP4 inhibitors had been attributed to a direct effect of the drugs on inflammatory cells expressing the enzyme. The present case, occurred during treatment with a GLP-1 receptor agonists, suggests a possibly different mechanism, mediated by GLP-1 receptor stimulation, which deserved further investigation.
Pubmed
Journal: American journal of human biology : the official journal of the Human Biology Council
March/9/2011
Abstract
Obesity and type 2 diabetes have become the major health problems in many industrialized countries. Here, I present the unconventional concept that a healthy organism maintains its systemic homeostasis by a "competent brain-pull", i.e., the brain's ability to properly demand glucose from the body, and that the underlying cause of obesity is "incompetent brain-pull." I describe the energy fluxes from the environment, through the body, toward the brain as the final consumer in a "supply chain" model. There is data-based support for the hypothesis, which states that under conditions of food abundance incompetent brain-pull will lead to build ups in the supply chain culminating in obesity and type 2 diabetes. There is also support for the related hypothesis, which states that under conditions of food deprivation, a competent brain-pull mechanism is indispensable for the continuation of the brain's high energy level. To experimentally determine how the competent brain-pull functions to demand for cerebral energy, healthy young men undergoing psychosocial stress were studied. It was found that the brain under stressful conditions demands for energy from the body by using a brain-pull mechanism, which is referred to as "cerebral insulin suppression" and in so doing it can satisfy its excessive needs during stress. This article gives an overview about the recent work on the "Selfish Brain" theory dealing with the maintenance of the cerebral and peripheral energy homeostasis.
Pubmed
Journal: Endocrine
March/7/2011
Abstract
Pancreatic β cells, stimulated by glucose, are known to synthesize and secrete insulin. As liver diseases are reported to cause diabetes mellitus, studies were conducted to determine the possibility of glucose-induced insulin synthesis in the liver cells. The glucose-induced insulin synthesis was determined by in vitro translation of mRNA from the hepatocytes. The cDNA from mRNA was prepared and sequence analysis was performed. Incubation of hepatocytes from the liver of adult mice (n=10) with glucose (0.02 M) resulted in the insulin synthesis [0.03 (mean)±0.006 (S.D.) μunits/mg/h] compared to the pancreatic β cells [0.04±0.004 μunits/mg/h]. Immunohistochemical study also demonstrated the glucose-induced synthesis of insulin in liver cells. Incubation of the mice hepatocytes with glucose resulted in the synthesis of insulin mRNA. The purified mRNA which was used to prepare cDNA resulted in the formation of proinsulin I and proinsulin II genes corresponding to 182 and 188 base pairs, respectively. Sequence analysis of the cDNA indicated that proinsulin I as well as proinsulin II gene could be involved in the synthesis of insulin by hepatocytes. These results suggested that insulin synthesis in both hepatic and pancreatic cells could be involved in the control of diabetes mellitus.
Pubmed
Journal: Diabetes care
January/17/2000
Abstract
OBJECTIVE
It has previously been demonstrated that the risk of hypoglycemia is low among otherwise healthy elderly fasted patients with type 2 diabetes taking oral sulfonylurea medications. Nevertheless, these agents do cause hypoglycemia in clinical practice, suggesting that accompanying factors must typically be present for hypoglycemia to occur. Ethanol is one putative risk factor that has not been evaluated as a mechanism for low blood glucose among sulfonylurea users. We hypothesized that low concentrations of ethanol would reduce blood glucose concentrations in elderly type 2 diabetic patients receiving sulfonylureas during a short-term fast.
METHODS
A total of 10 type 2 diabetic patients, aged 68 +/- 3 years and receiving 20 mg glyburide daily, participated in a prospective double-blind placebo-controlled in-patient study consisting of two 24-h fasts at least 1 week apart. During hours 14 and 15 of the fasting studies, subjects received intravenous infusions of either 4.35 mmol.kg-1.h-1 ethanol (equivalent to one or two alcoholic beverages) or saline placebo in random order. Ethanol, plasma glucose, insulin, and counterregulatory hormones were assessed very 30-60 min during the final 10 h of the fast.
RESULTS
Blood ethanol levels peaked at 17 +/- 2 mmol/l (the lower legal limit of intoxication in New Mexico) during the ethanol study. Plasma glucose concentrations did not differ at baseline (placebo 8.5 +/- 1.8 vs. ethanol 8.7 +/- 1.7 mmol/l; P = 0.50), but nadir plasma glucose was lower after the ethanol infusion compared with placebo (4.4 +/- 1.2 vs. 5.0 +/- 1.4 mmol/l; P = 0.01), and the absolute decline in plasma glucose was also greater during the ethanol study than the placebo study (4.7 +/- 0.9 vs. 3.6 +/- 1.2 mmol/l; P = 0.01). Counterregulatory hormone levels were increased during the ethanol study and nonesterified fatty acid concentrations were suppressed compared with the placebo study.
CONCLUSIONS
Low doses of ethanol predispose fasted elderly type 2 diabetic patients to low blood glucose during a short-term fast. This may be one of several mechanisms by which sulfonylurea-induced hypoglycemia occurs in elderly patients.
Pubmed
Journal: Diabetes, obesity & metabolism
September/29/2013
Abstract
OBJECTIVE
Intensive glycaemic control in type 2 diabetes achieved by insulin is generally accompanied by body weight gain. This study was performed to emphasize the meaning of caloric analysis of urine and faeces for energy balance.
METHODS
We measured energetic loss via urine and faeces during antihyperglycaemic treatment in male obese Zucker diabetic fatty (ZDF) rats. Rats were treated for 10 days with the sodium-glucose-linked transporter-2 (SGLT2) inhibitor AVE2268, with insulin glargine, with the GLP-1 receptor agonist lixisenatide and with the combination of insulin glargine and lixisenatide. Each study was accompanied by one lean (Fa/?) and one obese (fa/fa) untreated non-diabetic and diabetic control group, respectively. Blood glucose, body weight alterations and food assimilation efficiency were monitored.
RESULTS
In control ZDF rats, more than 12 g/day of pure glucose was urinarily excreted. In total, the energetic loss via urine exceeded 30% from total energy uptake. Insulin glargine treatment decreased urinary energetic loss, leading to a body weight gain of approximately 3 g/day. An almost body weight-neutral antihyperglycaemic treatment could be achieved with AVE2268 and lixisenatide. While lixisenatide reduced body weight gain via reduction of energy uptake, the SGLT2 inhibitor even increased urinary glucose and thus energy excretion. Combining insulin glargine with lixisenatide attenuated the anabolic effect of insulin resulting in weight neutrality.
CONCLUSIONS
Our data clearly show renal contribution to the body's energy control by urinary glucose excretion (UGE) during antidiabetic treatment. The undesired retained energy could be reduced via additional UGE or via simultaneous reduction of energy uptake and/or energy retention.
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