Drugs and hyperglycemia: A practical guide
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Nonalcoholic fatty liver disease (NAFLD), hepatic insulin resistance, and type 2 diabetes are all strongly associated and are all reaching epidemic proportions. Whether there is a causal link between NAFLD and hepatic insulin resistance is controversial. This review will discuss recent studies in both humans and animal models of NAFLD that have implicated increases in hepatic diacylglycerol (DAG) content leading to activation of novel protein kinase Cϵ (PKCϵ) resulting in decreased insulin signaling in the pathogenesis of NAFLD-associated hepatic insulin resistance and type 2 diabetes. The DAG-PKCϵ hypothesis can explain the occurrence of hepatic insulin resistance observed in most cases of NAFLD associated with obesity, lipodystrophy, and type 2 diabetes.
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Tight glycaemic control is key to reducing the risk of cardiovascular and microvascular complications in people with type 1 diabetes. 1 Standard treatment involves optimising insulin therapy to achieve an HbA 1c level of 48mmol/mol (6.5%) or lower. Although not licensed for use in type 1 diabetes, metformin is included in some clinical guidelines as adjuvant therapy for people with type 1 diabetes who are overweight and wish to improve glycaemic control while minimising the dose of insulin. 1,2 The REMOVAL study is the largest trial to date that has investigated the longer-term effects of metformin in people with type 1 diabetes. 3 Here, we consider the role of metformin in individuals with type 1 diabetes in light of these results and other study findings.
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To evaluate evidence from the medical literature that metformin is effective in preventing type 2 diabetes.Primary literature was accessed via a MEDLINE search (1966-December 2003) using the terms metformin, type 2 diabetes, and prevention.Two studies evaluated metformin's potential to prevent type 2 diabetes, finding that metformin maintained or reduced fasting blood glucose in non-diabetics. Recently, a large study by the Diabetes Prevention Program showed that metformin may reduce the incidence of diabetes. Researchers compared lifestyle changes, metformin therapy, and placebo groups. They found that both lifestyle changes (58%) and metformin therapy (31%) significantly reduced the occurrence of type 2 diabetes versus placebo.These studies provide evidence that metformin may reduce the occurrence of type 2 diabetes. Because long-term efficacy has not been determined, further studies are needed.
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Objective:to observe the curative effect of type 2 diabetes treated with novonorm combined with metformin. Method:34 patients diagnosed with type 2 diabetes on clinic were treated with novonorm combined with metformin for 6 months.Results:the comparison between fasting blood - glucose,postprandial plasma glucose and glycosylated hemoglobin before and after administration indicated significant difference(P0.05).Conclusion:the curative effect of type 2 diabetes treated with novonorm combined with metformin was prominent.
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Lactic acidosis
Gluconeogenesis
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Metformin has been used for the treatment of type 2 diabetes by suppressing hepatic gluconeogenesis. It has been shown that the subclinical inflammatory responses play important roles in the pathogenesis of type 2 diabetes. In the present study, we determined the effects of metformin on the levels of pro-inflammatory cytokines (i.e., IL-6, TNF-α, and MCP-1) and anti-inflammatory mediator IL-10 in blood and urine of patients with type 2 diabetes. There were 210 patients with type 2 diabetes, which were randomized into metformin (n = 112) and non-metformin (gliclazide, acarbose, and repaglinide, n = 98) groups. The levels of cytokines were measured by the ELISA.We found that metformin reduced the levels of IL-6 in blood and MCP-1 in urine, but increased IL-10 levels in blood of patients with type 2 diabetes. There were no significant differences of TNF-α between metformin and non-metformin groups. Furthermore, compared to individual drug treatment, metformin significantly reduced the levels of serum IL-6 and TNF-α, as well as urine MCP-1. When the patients were stratified based on the durations and doses of metformin, we found that there was only change (i.e., increase) in serum IL-10 levels in patients with metformin for more than 1 year compared to treatment for less than 1 year. Metformin (1.5 g) treatment reduced the urinary levels of MCP-1 as compared with dose of 1.0 g in patients with type 2 diabetes.Metformin reduces inflammatory responses without influence on renal function in type 2 diabetic patients.
Gliclazide
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Veterans Affairs
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We thank Prof. Dogru and colleagues for their interest in our recent article on the importance of adipocyte fatty acid binding protein (AFABP) in nonalcoholic fatty liver disease (NAFLD).1 It is now well accepted that NAFLD is the hepatic manifestation of the metabolic syndrome and as such is intimately associated with insulin resistance, visceral obesity, and dyslipidemia.2 Insulin resistance, which is a key characteristic of both conditions, has also been associated with NAFLD progression from simple steatosis to nonalcoholic steatohepatitis.3 We used the homeostasis model assessment of insulin resistance (HOMA-IR) to reflect the spectrum of insulin sensitivity. This index has been shown to correlate with the results of euglycemic-hyperinsulinemic clamp in patients without diabetes and with type 2 diabetes, including those treated with metformin and other oral hypoglycemic agents.4, 5 We were careful to exclude those taking thiazolidenediones, which have been shown to significantly affect circulating adipokine levels,6, 7 in contrast to sulfonylureas and metformin, which have not.7, 8 Type 2 diabetes eventually ensues in many subjects with increasing insulin resistance and is associated with more progressive fatty liver disease9; therefore, we decided not to exclude subjects with type 2 diabetes in our study. Although we agree it would be interesting to further subclassify subjects by glucose dysregulation status, the use of post hoc subset analysis is far less robust statistically and prone to type 2 error. We agree that metabolic variables and, in particular, measures of insulin resistance are important to consider when interpreting data on adipocytokines, which are intimately related to these factors. Indeed, our data showed the close association between both AFABP and lipocalin-2 to insulin resistance, body mass index, and waist circumference. To ensure our findings were independent of key confounders, we performed multivariate analysis for each histological endpoint in NAFLD using those factors significant on univariate analysis.1 We demonstrated that the association between AFABP and necroinflammatory and fibrotic activity is independent of abdominal obesity (the waist-hip ratio), cholesterol, high-density lipoprotein, and insulin resistance. For further clarity, as suggested by Prof. Dogru, we provide in Table 1 the relationship between AFABP and disease severity in NAFLD, directly controlled for insulin resistance and the key metabolic variables of body mass index, low-density lipoprotein, high-density lipoprotein, triglycerides, and glucose. This conclusively demonstrates that AFABP plays an important role in the pathogenesis of NAFLD independent of metabolic confounders. David van der Poorten*, Kerry-Lee Milner , Donald J. Chisholm , Jacob George*, * Storr Liver Unit, Westmead Millennium Institute, University of Sydney, Sydney, Australia, Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia.
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