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)

A 38-year-old otherwise healthy man presented with hepatic failure (aspartate aminotransferase of 7212 U/L, alanine aminotransferase of 6629 U/L, total and direct bilirubin of 10.7 mg/dL) and acute renal failure (creatinine of 11.6 mg/dL and blood urea nitrogen of 42 mg/dL), which required hemodialysis when the creatinine increased to 21 mg/dL, with a blood urea nitrogen of 115 mg/dL, and the patient became oliguric. On admission, this patient also had a lipase of 1833 U/L, amylase of 211 U/L, glucose of 210 mg/dL, and reactive IgM antibody for acute hepatitis A. The hepatitis and acute renal failure resolved in 3 months, but this patient continues to have type II diabetes mellitus 7 years after the hepatitis A infection. This case illustrates that hepatitis A infection may be severe with liver failure, acute renal failure, and permanent diabetes mellitus as sequale of this infection.
 ...
PMID:Hepatitis A-induced diabetes mellitus, acute renal failure, and liver failure. 1037 44

Today, obesity is the most important modifiable risk factor for type 2 diabetes. An excess of body fat is associated with a deterioration of glucose utilisation and promotes the development of type 2 diabetes, particularly in those with a genetic predisposition for the disease. It is also well established that a reduction of excess body fat improves insulin sensitivity and can prevent the conversion to diabetes. In those with overt diabetes, weight loss usually ameliorates glycaemic control and associated metabolic disturbances. Among the pharmacological agents that are used for the treatment of type 2 diabetes only metformin has a weak weight-lowering activity and is considered as the drug of choice for adjunct pharmacotherapy in obese diabetic subjects. A few studies also suggest that acarbose can induce a modest weight reduction in such patients. In contrast, sulphonylurea and insulin treatment is frequently accompanied by substantial weight gain which should be taken into consideration when these drugs are used. Another approach to improve metabolic control in obese type 2 diabetic patients is the use of weight-lowering agents. The new serotonin and noradrenaline reuptake inhibitor sibutramine promotes weight loss which subsequently leads to improved glycaemic control. Orlistat, a lipase inhibitor, is also able to ameliorate metabolic control in such patients due to its weight-lowering potential. As obesity remains a therapeutic challenge in most type 2 diabetic subjects, weight management drugs may represent an alternative or supplement to antidiabetic agents. Moreover, weight management agents have the advantage that they have additional favourable effects on associated cardiovascular risk factors.
 ...
PMID:The impact of pharmacotherapy on weight management in type 2 diabetes. 1045 66

Obesity is a well-known risk factor for the development of Type 2 diabetes mellitus. The management of the obese diabetic patient remains a challenge for the clinician but, in any case, weight reduction should be considered as a key objective. In this respect, several antiobesity drugs have demonstrated potential. However, while fenfluramine and dexfenfluramine have been shown to promote weight loss and to directly improve insulin sensitivity, being two mechanisms contributing to better blood glucose control in obese Type 2 diabetic patients, they were recently withdrawn due to safety problems. Sibutramine, a new selective norepinephrine and serotonin reuptake inhibitor, promotes weight loss by decreasing food intake, an effect which leads to a mild improvement (significant in patients losing > or =5% of initial body weight) of blood glucose control in obese diabetic patients. Similarly, orlistat, a selective gastrointestinal lipase inhibitor which increases faecal fat losses, enhances diet-induced weight reduction and improves both blood glucose control and vascular risk profile, especially dyslipidaemia, in obese Type 2 diabetic patients. Further studies are required to better identify good responders to pharmacotherapy and specify the role of antiobesity agents in the overall long-term management of obese subjects with Type 2 diabetes. Other novel pharmacological approaches deserve further consideration, for instance beta-3 agonists aiming to increase energy expenditure, drugs interfering with tumor necrosis factor-alpha (TNF-alpha) or free fatty acid release by the adipose tissue or agents that slow gastric emptying. However, until now, results regarding efficacy and/or safety have been disappointing or preliminary in humans.
 ...
PMID:Antiobesity pharmacotherapy in the management of type 2 diabetes. 1075 51

Current agents for the treatment of Type 2 diabetes mellitus improve the metabolic profile but do not reinstate normality. They also reduce chronic diabetic complications, but they do not eliminate them. Thus, new agents with novel actions are required to complement and extend the capabilities of existing treatments. Insulin resistance and beta-cell failure, which are crucial components in the pathogenesis of Type 2 diabetes, remain the underlying targets for new drugs. Recently introduced agents include a short-acting non-sulphonylurea insulin-releaser, repaglinide, which synchronizes insulin secretion with meal digestion in order to reduce post-prandial hyperglycaemia. The thiazolidinedione drugs, troglitazone, rosiglitazone and pioglitazone represent a new class of agonists for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). PPARgamma increases the transcription of certain insulin-sensitive genes, thereby improving insulin sensitivity. The intestinal lipase inhibitor orlistat and the satiety-inducer sibutramine are new weight-reducing agents that may benefit glycaemic control in obese Type 2 diabetes patients. Several further new insulin-releasing agents, and agents to retard carbohydrate digestion and modify lipid metabolism stand poised to enter the market. The extent to which they will benefit glycaemic control remains to be seen. However, the prospect of permanently arresting or reversing the progressive deterioration of Type 2 diabetes continues to evade therapeutic capture.
 ...
PMID:New agents for Type 2 diabetes. 1076 69

Orlistat is a novel, noncentrally acting antiobesity agent that selectively inhibits gastrointestinal lipase activity, thereby reducing the absorption of dietary fat by approximately one-third. In a series of 1- and 2-yr randomized, placebo-controlled trials of obese subjects, treatment with orlistat in combination with a mildly calorie-restricted diet consistently produced significantly greater mean weight loss than diet alone. More orlistat-treated subjects than placebo recipients achieved clinically meaningful weight reduction (> or =5% or > or =10% of initial body weight) after 1 and 2 yr. Orlistat was also associated with a significant reduction in the regain of lost weight during long-term treatment. In addition, orlistat therapy resulted in significant improvements in several cardiovascular risk factors including serum total and low-density lipoprotein-cholesterol, serum insulin levels, systolic and diastolic blood pressure, and waist circumference. Furthermore, obese subjects with type 2 diabetes achieved a significantly greater decrease in body weight with orlistat compared with placebo, as well as significant improvements in HbA1c and fasting glucose levels. Among subjects with impaired glucose tolerance, orlistat compared with placebo reduced the proportion who developed type 2 diabetes. Conversely, orlistat increased the proportion of subjects who achieved a normalization of glucose tolerance. Orlistat acts locally in the gastrointestinal tract and is only minimally absorbed. In long-term clinical trials, orlistat was well tolerated by both diabetic and nondiabetic subjects.
 ...
PMID:Orlistat: selective inhibition of caloric absorption can affect long-term body weight. 1118 21

Maturity-onset diabetes of the young type 3 (MODY3) is caused by haploinsufficiency of hepatocyte nuclear factor-1alpha (encoded by TCF1). Tcf1-/- mice have type 2 diabetes, dwarfism, renal Fanconi syndrome, hepatic dysfunction and hypercholestrolemia. Here we explore the molecular basis for the hypercholesterolemia using oligonucleotide microchip expression analysis. We demonstrate that Tcf1-/- mice have a defect in bile acid transport, increased bile acid and liver cholesterol synthesis, and impaired HDL metabolism. Tcf1-/- liver has decreased expression of the basolateral membrane bile acid transporters Slc10a1, Slc21a3 and Slc21a5, leading to impaired portal bile acid uptake and elevated plasma bile acid concentrations. In intestine and kidneys, Tcf1-/- mice lack expression of the ileal bile acid transporter (Slc10a2), resulting in increased fecal and urinary bile acid excretion. The Tcf1 protein (also known as HNF-1alpha) also regulates transcription of the gene (Nr1h4) encoding the farnesoid X receptor-1 (Fxr-1), thereby leading to reduced expression of small heterodimer partner-1 (Shp-1) and repression of Cyp7a1, the rate-limiting enzyme in the classic bile acid biosynthesis pathway. In addition, hepatocyte bile acid storage protein is absent from Tcf1-/- mice. Increased plasma cholesterol of Tcf1-/- mice resides predominantly in large, buoyant, high-density lipoprotein (HDL) particles. This is most likely due to reduced activity of the HDL-catabolic enzyme hepatic lipase (Lipc) and increased expression of HDL-cholesterol esterifying enzyme lecithin:cholesterol acyl transferase (Lcat). Our studies demonstrate that Tcf1, in addition to being an important regulator of insulin secretion, is an essential transcriptional regulator of bile acid and HDL-cholesterol metabolism.
 ...
PMID:Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism. 1127 18

The aim of this study was to delineate the role of lipoprotein lipase (LPL) activity in the kinetic alterations of high density lipoprotein (HDL) metabolism in patients with type II diabetes mellitus compared with controls. The kinetics of HDL were studied by endogenous labeling of HDL apolipoprotein AI (HDL-apo AI) using a primed infusion of D(3)-leucine. The HDL-apo AI fractional catabolic rate (FCR) was significantly increased (0.32 +/- 0.07 vs. 0.23 +/- 0.05 pool/day; P < 0.01), and HDL composition was changed [HDL cholesterol, 0.77 +/- 0.16 vs. 1.19 +/- 0.37 mmol/L (P < 0.05); HDL triglycerides, 0.19 +/- 0.12 vs. 0.10 +/- 0.03 mmol/L (P < 0.05)] in diabetic patients compared with healthy subjects. HDL-apo AI FCR was correlated to plasma and HDL triglyceride concentrations (r = 0.82; P < 0.05 and r = 0.80; P < 0.05, respectively) and to homeostasis model assessment (r = 0.78; P < 0.05). Postheparin plasma LPL activity was decreased in type II diabetes (6.8 +/- 2.8 vs. 18.1 +/- 5.2 micromol/mL postheparin plasma.h; P < 0.005) compared with that in healthy subjects and was correlated to the FCR of HDL-apo AI (r = -0.63; P < 0.05). LPL activity was also correlated with HDL cholesterol (r = 0.78; P < 0.05), plasma and HDL triglycerides (r = -0.87; P < 0.005 and r = -0.83; P < 0.05, respectively), and homeostasis model assessment (r = -0.79; P < 0.05). In addition, the LPL to hepatic lipase ratio was correlated with the catabolic rate of HDL (r = -0.76; P < 0.06). These results suggest that a decrease in the LPL to hepatic lipase ratio in type II diabetes mellitus, mainly related to lowered LPL activity, could induce an increase in HDL catabolism. These alterations in HDL kinetics in type II diabetes proceed to some extent from changes in their composition, probably linked to an increase in triglyceride transfer from very low density lipoprotein particles, in close relationship with LPL activity and resistance to insulin.
 ...
PMID:In vivo evidence for the role of lipoprotein lipase activity in the regulation of apolipoprotein AI metabolism: a kinetic study in control subjects and patients with type II diabetes mellitus. 1134 92

Genetic variation in the hepatic lipase (HL) gene (LIPC) promoter is an important determinant of HL activity in Caucasians. As HL activity is increased in patients with type 2 diabetes mellitus, we have investigated whether the -514 C-to-T polymorphism acted independently of type 2 diabetes to regulate HL activity. The frequency of this polymorphism and its effect on plasma HL activity and lipids were examined in 203 Chinese patients with type 2 diabetes and 205 controls. The frequency of the T allele was 0.343 and 0.376 in male and female diabetic patients, respectively, compared with 0.371 and 0.372 in male and female controls. The effect of LIPC genotype on HL activity was similar between men and women, and between diabetic patients and non-diabetic controls, with the lowest HL activity being found in those subjects with the TT genotype. On multivariate analysis, gender, LIPC genotype, the presence of type 2 diabetes and body mass index were independent predictors of HL activity, accounting for 22, 9, 5 and 3%, respectively, of the variance in HL activity (whole model adjusted R(2)=0.39, P<0.0001). The T allele was associated with higher high-density lipoprotein in the controls but not in the diabetic patients, and no associations were found between LIPC genotype and low-density lipoprotein subfractions in either groups. In conclusion, despite the higher frequency of the T allele in Chinese than in Caucasians, gender was the best predictor for HL activity, with LIPC gene polymorphism and type 2 diabetes making relatively smaller contributions to the variation in HL activity.
 ...
PMID:Effects of gender, hepatic lipase gene polymorphism and type 2 diabetes mellitus on hepatic lipase activity in Chinese. 1142 26

In this review we present the agents that are in use in the treatment of type 2 diabetes. Sulfonylureas of the 1st and 2nd generation increase insulin secretion but can induce hyperinsulinemia and sometimes prolonged hypoglycemia. Glimepiride is a new 3rd generation sulfonylurea with some advantages over the other members of this group, such as a lower risk of hypoglycemia, no interaction with cardiovascular KATP-channels and a possibility that it may increase insulin sensitivity. There are also newer insulin secretagogues (such as neteglinide and repaglinide) with a rapid onset of action on the beta-cell, therefore inducing a more physiological profile of insulin secretion during meals. The category of insulin sensitizers includes metformin and thiazolidinediones. Metformin effectively reduces hyperglycemia, hyperlipidemia and macroangiopathy in patients with type 2 diabetes. This agent increases the sensitivity of the liver and peripheral tissues to insulin and, therefore, it could be considered as a drug of choice for the prevention of type 2 diabetes. Thiazolidinediones (rosiglitazone and pioglitazone) increase the sensitivity of the tissues to insulin. This mechanism of action makes them powerful therapeutic tools for the treatment of type 2 diabetes (and possibly other insulin resistant states) either alone or in combination with other oral agents. The category of agents that interfere with the absorption of glucose and lipids includes alpha-glucosidase inhibitors (acarbose and miglitol) and lipase inhibitors (or-listat). alpha-Glucocidase inhibitors improve the time relationship between plasma insulin and glucose increases after a meal. Therefore, these agents may be used in the treatment of patients with type 2 diabetes, either alone at a very early stage of this disease (when insulin secretion is still adequate), or in combination with insulin secretagogues. alpha-Glucosidase inhibition may also prove useful as a supplement to insulin therapy in patients with type 1 diabetes mellitus. The inhibitor of gastrointestinal lipase orlistat may prove a useful adjunct to hypocaloric diets in patients with type 2 diabetes and obesity.
 ...
PMID:Oral hypoglycemic agents: insulin secretagogues, alpha-glucosidase inhibitors and insulin sensitizers. 1146 May 77

Type 2 diabetes is characterised by both impaired insulin secretion and insulin resistance but their relative contribution to the development of hyperglycaemia may differ due to heterogeneity of the disease. Under most circumstances, insulin resistance is the earliest detectable defect in pre-diabetic individuals but it is not known whether this is the primary defect or secondary to other abnormalities such as abdominal obesity with excessive free fatty acid turnover and increased lipid deposits in muscle. Initially, enhanced insulin secretion can compensate for the insulin resistance but early phase insulin secretion is impaired. In the transition from normal to impaired and diabetic glucose tolerance, insulin sensitivity deteriorates about 40% whereas insulin secretion deteriorates 3-4 fold. In addition to insulin resistance, the metabolic syndrome includes hypertension, dyslipidaemia, obesity and microalbuminuria. In patients with manifest diabetes, chronic hyperglycaemia can result in further deterioration of insulin sensitivity and secretion (glucotoxicity), which is aggravated by elevated free fatty acids (lipotoxicity). Abdominal obesity and insulin resistance are strongly correlated and studies have aimed at understanding the genetic basis. Candidate genes for the metabolic syndrome include those for the beta 3-adrenergic receptor, lipoprotein lipase, hormone sensitive lipase, peroxisome proliferator-activated receptor-gamma, insulin receptor substrate-1 and glycogen synthase. Therefore, type 2 diabetes is multigenic and appears to represent a collision between thrifty genes and an affluent society. Successful management will require treatments targeted at defects of both insulin secretion and insulin resistance.
 ...
PMID:Pathogenesis of type 2 diabetes: the relative contribution of insulin resistance and impaired insulin secretion. 1196 29


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>