Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin exerts wide variety of biological effects through interaction with its specific receptor, which belongs to a large family of receptor tyrosine kinases. The activated insulin receptor phosphorylates the intracellular substrate IRS protains, which then bind various signalling molecules that contain Src homology 2 domains. The first downstram molecule that was shown to associate with IRS protains is PI3-kinase. PI3-kinase contributes to a wide variety of biological actions. Both Akt(PKB), a serine-threonine kinase with a PH domain, and atypical PKC(PKC zeta, PKC lambda) have been implicated as downstream effectors of PI3-kinase. Insulin resistance contributes to the pathogenesis of NIDDM. Both primary, genetically, and secondary, environmentally factors are important for insulin resistance. The secondary factors include hyperglycemia, hyperlipidemia, obesity, TNF alpha, FFA(free fatty acid).
 ...
PMID:[Insulin signalling system and mechanism of insulin resistance]. 1070 48

Obesity is considered as the most important risk factor for type 2 diabetes. We will briefly discuss why does obesity predispose to diabetes, when does diabetes occur in obese subjects and who among obese individuals is particularly prone to develop diabetes. Obesity, especially intraabdominal adiposity, is associated with increased FFA plasma concentrations which exert a major negative effect on insulin sensitivity at both muscular and hepatic sites. Various metabolic, haemodynamic and hormonal theories have been proposed to explain insulin resistance in obese subjects. A specific role of TNF-alpha has been recently suggested. However, besides insulin resistance, defective insulin secretion is a prerequisie for the development of overt type 2 diabetes. Both lipotoxicity and glucotoxicity may initiate and perpetuate a vicious circle responsible for the metabolic deterioration. Diabetes occurs as a late phenomenon in obesity and is preceded by years of impaired glucose tolerance. The progression to diabetes is heralded by an inability of the B cell to maintain its previously high rate of insulin secretion in response to glucose in face of insulin resistance. This propensity to develop type 2 diabetes may be genetically determined and/or triggered by environmental factors. The evolution from obesity to diabetes represents a continuum that progresses through different phases in which defects in both insulin action and insulin secretion play a critical interaction and must be looked at in concert.
 ...
PMID:From obesity to diabetes: why, when and who? 1078 2

Insulin is released in a high-frequency pulsatile secretory pattern, which is reflected as quantifiable oscillations in peripheral circulating insulin concentrations. Type 2 diabetes mellitus is characterized by a broad spectrum of abnormalities in beta-cell function, including disturbed pulsatile insulin secretion as assessed by autocorrelation analysis. To achieve further insight into beta-cell pathophysiology in type 2 diabetes, we examined the orderliness of the baseline serum insulin time series (blood collection every minute for 75 minutes) in 16 type 2 diabetics (fasting plasma glucose, 170 +/- 10 mg/dL [mean +/- SE]; serum free fatty acid [FFA], 0.794 +/- 0.083 mmol/L; and known diabetes duration, 6 +/- 2 years) and 15 healthy controls (serum FFA, 0.523 +/- 0.055 mmol/L). We used approximate entropy (ApEn), a recently introduced scale- and model-independent measure of serial irregularity. ApEn was significantly increased in the type 2 diabetics compared with the controls (0.671 +/- 0.016 v 0.653 +/- 0.008, P = .04), indicating more irregular serum insulin time series in diabetics. Autocorrelation also discriminated between groups, although only when the data were pooled. Interestingly, an inverse relationship between ApEn and serum FFA was observed in the controls (r = -.63, P = .01) and diabetics (r = -.65, P < .01), whereas no relationships were found between ApEn and the age, body mass index (BMI), or plasma glucose. In conclusion, type 2 diabetes is characterized by an increased disorderliness of the fasting serum insulin time series, strongly suggesting perturbed rapid oscillatory insulin release. An inverse relationship between ApEn and fasting serum FFA among both groups might suggest a hitherto unknown stabilizing action of FFA on the high-frequency pulsatile insulin release process. This hypothesis needs to be tested in experimental designs that more specifically focus on this issue, eg, during changes in serum FFA.
 ...
PMID:Irregular circulating insulin concentrations in type 2 diabetes mellitus: an inverse relationship between circulating free fatty acid and the disorderliness of an insulin time series in diabetic and healthy individuals. 1117 73

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists, including the glitazone class of drugs, are insulin sensitizers that reduce glucose and lipid levels in patients with type 2 diabetes mellitus. To more fully understand the molecular mechanisms underlying their therapeutic actions, we have characterized the effects of the potent, tyrosine-based PPAR gamma ligand GW1929 on serum glucose and lipid parameters and gene expression in Zucker diabetic fatty rats. In time-course studies, GW1929 treatment decreased circulating FFA levels before reducing glucose and triglyceride levels. We used a comprehensive and unbiased messenger RNA profiling technique to identify genes regulated either directly or indirectly by PPAR gamma in epididymal white adipose tissue, interscapular brown adipose tissue, liver, and soleus skeletal muscle. PPAR gamma activation stimulated the expression of a large number of genes involved in lipogenesis and fatty acid metabolism in both white adipose tissue and brown adipose tissue. In muscle, PPAR gamma agonist treatment decreased the expression of pyruvate dehydrogenase kinase 4, which represses oxidative glucose metabolism, and also decreased the expression of genes involved in fatty acid transport and oxidation. These changes suggest a molecular basis for PPAR gamma-mediated increases in glucose utilization in muscle. In liver, PPAR gamma activation coordinately decreased the expression of genes involved in gluconeogenesis. We conclude from these studies that the antidiabetic actions of PPAR gamma agonists are probably the consequence of 1) their effects on FFA levels, and 2), their coordinate effects on gene expression in multiple insulin-sensitive tissues.
 ...
PMID:Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor gamma activation has coordinate effects on gene expression in multiple insulin-sensitive tissues. 1118 44

ABSTRACT Because prenatal and perinatal undernutrition are associated with type 2 diabetes later in life, we posed the question whether nutrient deprivation during puberty would also result in a decreased ability to secrete insulin. Chronically catheterized, unstressed Sprague Dawley rats, fed ad libitum, were studied before puberty (Pre, n = 14) and after puberty (Post, n = 8). Moderately caloric-restricted rats (fed 70% of the control diet, n = 9), were studied after puberty. Insulin secretion was assessed using a hyperglycemic clamp at a glucose concentration of 300 mg/dL, or with a primed continuous infusion of intralipid (plasma FFA levels approximately 1.5 mM) at a plasma glucose concentration of 200 mg/dL. Stimulated insulin levels increased in Post rats by 3- to 4-fold compared with Pre rats (from 4.6 +/- 0.4 ng/mL Pre to 12.8 +/- 0.7 ng/mL Post, and from 4.5 +/- 0.4 ng/mL Pre to 15.8 +/- 0.7 ng/mL Post, respectively, p < 0.001, at a glucose concentration of 300 mg/dL, and 200 mg/dL with intralipid). Caloric restriction prevented any rise in insulin secretion (3.8 +/- 0.5 and 4.6 +/- 0.5 ng/mL in the caloric-restricted rats at glucose concentrations of 300 mg/dL and 200 mg/dL with intralipid, respectively). A semiquantitative reverse-transcriptase PCR procedure was used to assess basal and stimulated insulin mRNA levels. Caloric restriction did not compensate by enhancing insulin mRNA levels in response to glucose stimulation. Moderate food deprivation during puberty reduced the capacity of the pancreas to secrete insulin in response to different nutrient stimuli. We hypothesize that puberty has an important role in beta-cell maturation and any major nutrient modification may have deleterious consequences later in life.
 ...
PMID:Food deprivation limits insulin secretory capacity in postpubertal rats. 1126 28

Abnormalities observed in intermediary metabolism may be related to the pathogenesis of obesity-related diseases such as type 2 diabetes. Glycerol and lactate production was estimated in the sc adipose tissue of two anatomical regions of 10 lean (LW), 10 obese (OW), and 10 matched diabetic (DW) black urban women. This was done with the sc microdialysis technique and combined with adipose tissue blood flow (ATBF) rates calculated from (133)Xe clearance. Biochemical measurements were made in the postabsorptive and postprandial state. Bioimpedance and computed tomography scans were used to define body composition. DW present with more visceral fat (DW, 138 +/- 5.0; OW, 66.6 +/- 5.0 cm; P < 0.01). This was associated with elevated free testosterone levels (DW, 1.21 +/- 0.1; OW, 0.75 +/- 0.1 nmol/L; P < 0.05). The fasting FFA, glycerol, and lactate levels increased across the three groups (LW < OW < DW). During the oral glucose tolerance test, glucose levels were elevated in DW, with higher insulin levels [0 h: DW, 207 +/- 8.6; OW, 100 +/- 7.2 pmol/L (P < 0.01); 1 h: DW, 410 +/- 15.2; OW, 320 +/- 10.9 pmol/L (P < 0.05)], but with a flat Cpeptide response (1 h: DW, 932 +/- 40; OW, 1764 +/- 40 pmol/L; P < 0.05). Plasma lactate levels increased significantly in LW and OW at 1 h (P < 0.001), but remained lower in LW vs. OW for all time points. ATBF was highest in LW [abdominal, 0 h: DW, 4.5 +/- 0.2; OW, 1.7 mL/100 g.min (P < 0.01); femoral, 0 h: DW, 3.4 +/- 0.2; OW, 1.8 +/- 0.3 mL/100 g.min (P < 0.01)]. ATBF did not increase in DW during the oral glucose tolerance test. Glycerol release (GR) was used to assess the lipolytic rate and was highest in LW in the abdominal area [0 h: LW, 1.7 +/- 0.2; OW, 1.1 +/- 0.2 micromol/kg.min (P < 0.05); DW, 0.78 +/- 0.05 micromol/kg.min (P < 0.05 vs. OW)]. By contrast, GR was higher in the femoral area of OW (0 h: OW, 1.6 +/- 0.2; LW, 1.15 +/- 0.1 micromol/kg.min; P < 0.05). Regional differences were observed for GR in both OW and DW (femoral > abdominal). Lactate release (LR) was low in DW [abdominal, 0 h: DW, 3.5 +/- 0.4; OW, 7.8 +/- 1.0 micromol/kg.min (P < 0.001); femoral, 0 h: DW, 3.1 +/- 0.3; OW, 9.0 +/- 0.9 micromol/kg.min (P < 0.001)]. LR was appropriately low for body fat mass in LW, with a brisk increase between 0 and 1.5 h. A negative correlation exists between GR (abdominal area) and insulin levels in the postabsorptive state (P < 0.0001). In conclusion, 1) the fasting lipolytic rate is associated with insulin levels; 2) OW and DW have more adipose tissue insulin resistance than LW; 3) OW and DW have a brisker lipolysis in the femoral area; and 4) in DW, higher visceral mass is associated with elevated free testosterone and FFA concentrations. Obesity in the black population is therefore characterized by a marked degree of adipose tissue lipolysis. This degree of resistance together with increasing body fat mass may predispose the obese women to developing type 2 diabetes. Once this disease is established, the onset of adipose tissue vascular insulin resistance will sustain ongoing insulin resistance, even in the presence of relative insulinopenia.
 ...
PMID:Lactate and glycerol release from adipose tissue in lean, obese, and diabetic women from South Africa. 1144 4

In patients with type 2 diabetes, a strong correlation between accumulation of intramuscular triclycerides (TGs) and insulin resistance has been found. The aim of the present study was to determine whether there is a causal relation between intramuscular TG accumulation and insulin sensitivity. Therefore, in mice with muscle-specific overexpression of human lipoprotein lipase (LPL) and control mice, muscle TG content was measured in combination with glucose uptake in vivo, under hyperinsulinemic-euglycemic conditions. Overexpression of LPL in muscle resulted in accumulation of TGs in skeletal muscle (85.5 +/- 33.3 vs. 25.7 +/- 23.1 micromol/g tissue in LPL and control mice, respectively; P < 0.05). During the hyperinsulinemic clamp study, there were no differences in plasma glucose, insulin, and FFA concentrations between the two groups. Moreover, whole-body, as well as skeletal muscle, insulin-mediated glucose uptake did not differ between LPL-overexpressing and wild-type mice. Surprisingly, whole-body glucose oxidation was decreased by approximately 60% (P < 0.05), whereas nonoxidative glucose disposal was increased by approximately 50% (P < 0.05) in LPL-overexpressing versus control mice. In conclusion, overexpression of human LPL in muscle increases intramuscular TG accumulation, but does not affect whole-body or muscle-specific insulin-mediated uptake, findings that argue against a simple causal relation between intramuscular TG content and insulin resistance.
 ...
PMID:In muscle-specific lipoprotein lipase-overexpressing mice, muscle triglyceride content is increased without inhibition of insulin-stimulated whole-body and muscle-specific glucose uptake. 1167 38

Skeletal muscle insulin resistance (IR) is typically severe in type 2 diabetes mellitus (DM). However, the factors that account for interindividual differences in the severity of IR are not well understood. The current study was undertaken to examine the respective roles of plasma FFA, regional adiposity, and other metabolic factors as determinants of the severity of skeletal muscle IR in type 2 DM. Twenty-three subjects (12 women and 11 men) with type 2 DM underwent positron emission tomography imaging using [18F]2-fluoro-2-deoxyglucose during euglycemic insulin infusions (120 mU/min x m2) to measure skeletal muscle IR, using Patlak analysis of the tissue activity curves. Body composition analysis included body mass index, fat mass, and fat-free mass by dual energy x-ray tomography, and computed tomography determinations of visceral adiposity, thigh adipose tissue distribution, and muscle composition. Body mass index, fat mass, subfascial adiposity in the thigh, and visceral adipose tissue (VAT) were all significantly related to skeletal muscle IR (r = -0.48 to -0.63; P < 0.01). However, the strongest simple correlate of IR in skeletal muscle was insulin-suppressed plasma FFA (r = -0.81; P < 0.001). VAT was the sole component of adiposity that significantly correlated with insulin-suppressed plasma FFA concentration (r = 0.64; P < 0.001). These findings indicate that the severity of skeletal muscle IR in type 2 DM is closely related to the IR of suppressing lipolysis and that plasma fatty acids and VAT are key elements mediating the link between obesity and skeletal muscle IR in type 2 DM.
 ...
PMID:Plasma fatty acids, adiposity, and variance of skeletal muscle insulin resistance in type 2 diabetes mellitus. 1170 15

Our understanding of apolipoprotein A-II (apoA-II) physiology is much more limited than that of apoA-I. However, important and rather surprising advances have been produced, mainly through analysis of genetically modified mice. These results reveal a positive association of apoA-II with FFA and VLDL triglyceride plasma concentrations; however, whether this is due to increased VLDL synthesis or to decreased VLDL catabolism remains a matter of controversy. As apoA-II-deficient mice present a phenotype of insulin hypersensitivity, a function of apoA-II in regulating FFA metabolism seems likely. Studies of human beings have shown the apoA-II locus to be a determinant of FFA plasma levels, and several genome-wide searches of different populations with type 2 diabetes have found linkage to an apoA-II intragenic marker, making apoA-II an attractive candidate gene for this disease. The increased concentration of apoB-containing lipoproteins present in apoA-II transgenic mice explains, in part, why these animals present increased atherosclerosis susceptibility. In addition, apoA-II transgenic mice also present impairment of two major HDL antiatherogenic functions: reverse cholesterol transport and protection of LDL oxidative modification. The apoA-II locus has also been suggested as an important genetic determinant of HDL cholesterol concentration, even though there is a major species-specific difference between the effects of mouse and human apoA-II. As antagonizing apoA-I antiatherogenic actions can hardly be considered the apoA-II function in HDL, this remains a topic for future investigations. We suggest that the existence of apoA-II or apoA-I in HDL could be an important signal for specific interaction with HDL receptors such as cubilin or heat shock protein 60.
 ...
PMID:Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein. 1171 42

The EDS (early-onset diabetes in suncus) colony was developed as a new laboratory colony of the musk shrew and is characterized by a high incidence of early-onset spontaneous non-insulin dependent diabetes mellitus (NIDDM). We examined blood lipid (triglyceride [TG], total cholesterol [TC], phospholipid [PL], free fatty acid [FFA]) and liver lipid (TG, TC, PL) concentrations to investigate the features of lipid metabolism in these animals. All lipid concentrations examined both in blood and liver of the diabetic shrews had a tendency toward higher values than those in non-diabetic shrews. The PL concentration was the only parameter that barely showed a significant difference. Values for all blood lipid concentrations in diabetic shrews at 7-9 months tended to be higher than those of 2-month-old diabetic shrews, although the difference was not significant. These findings indicate that diabetic EDS shrews exhibit a much milder defect of lipid metabolism induced by NIDDM than other rodent models.
 ...
PMID:Blood and liver lipid concentrations in EDS shrews exhibiting spontaneous non-insulin dependent diabetes mellitus (NIDDM). 1176 46


<< Previous 1 2 3 4 5 6 7 8 9 Next >>