Type 2 Diabetes Mellitus: Update on Diagnosis, Pathophysiology, and Treatment

Mahler, Richard J.; Adler, Michaël

doi:10.1210/jcem.84.4.5612

Cited by 133 publications

(47 citation statements)

References 107 publications

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“…It seems to be an ongoing process hardly influenced by concomitant glucose lowering treatment (38). Loss of first-phase insulin response to glucose is an early ␤-cell defect, followed by a weakened basal and second-phase insulin output as the disease progresses (39,40). This, combined with an abnormal circadian glucagon secretory pattern (5,33) and diminished ability of hyperglycemia to suppress glucagon secretion, demonstrates the necessity for opposing both the ␣-and ␤-cell malfunction in the treatment of type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

One Week’s Treatment With the Long-Acting Glucagon-Like Peptide 1 Derivative Liraglutide (NN2211) Markedly Improves 24-h Glycemia and α- and β-Cell Function and Reduces Endogenous Glucose Release in Patients with Type 2 Diabetes

et al. 2004

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Glucagon-like peptide 1 (GLP-1) is potentially a very attractive agent for treating type 2 diabetes. We explored the effect of short-term (1 week) treatment with a GLP-1 derivative, liraglutide (NN2211), on 24-h dynamics in glycemia and circulating free fatty acids, islet cell hormone profiles, and gastric emptying during meals using acetaminophen. Furthermore, fasting endogenous glucose release and gluconeogenesis (3-3 Hglucose infusion and 2 H 2 O ingestion, respectively) were determined, and aspects of pancreatic islet cell function were elucidated on the subsequent day using homeostasis model assessment and first-and second-phase insulin response during a hyperglycemic clamp (plasma glucose ϳ16 mmol/l), and, finally, on top of hyperglycemia, an arginine stimulation test was performed. For accomplishing this, 13 patients with type 2 diabetes were examined in a double-blind, placebo-controlled crossover design. Liraglutide (6 g/kg) was administered subcutaneously once daily. Liraglutide significantly reduced the 24-h area under the curve for glucose (P ‫؍‬ 0.01) and glucagon (P ‫؍‬ 0.04), whereas the area under the curve for circulating free fatty acids was unaltered. Twenty-four-hour insulin secretion rates as assessed by deconvolution of serum C-peptide concentrations were unchanged, indicating a relative increase. Gastric emptying was not influenced at the dose of liraglutide used. Fasting endogenous glucose release was decreased (P ‫؍‬ 0.04) as a result of a reduced glycogenolysis (P ‫؍‬ 0.01), whereas gluconeogenesis was unaltered. First-phase insulin response and the insulin response to an arginine stimulation test with the presence of hyperglycemia were markedly increased (P < 0.001), whereas the proinsulin/insulin ratio fell (P ‫؍‬ 0.001). The disposition index (peak insulin concentration after intravenous bolus of glucose multiplied by insulin sensitivity as assessed by homeostasis model assessment) almost doubled during liraglutide treatment (P < 0.01). Both during hyperglycemia per se and after arginine exposure, the glucagon responses were reduced during liraglutide administration (P < 0.01 and P ‫؍‬ 0.01). Thus, 1 week's treatment with a single daily dose of the GLP-1 derivative liraglutide, operating through several different mechanisms including an ameliorated pancreatic islet cell function in individuals with type 2 diabetes, improves glycemic control throughout 24 h of daily living, i.e., prandial and nocturnal periods. This study further emphasizes GLP-1 and its derivatives as a promising novel concept for treatment of type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

One Week’s Treatment With the Long-Acting Glucagon-Like Peptide 1 Derivative Liraglutide (NN2211) Markedly Improves 24-h Glycemia and α- and β-Cell Function and Reduces Endogenous Glucose Release in Patients with Type 2 Diabetes

et al. 2004

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“…Insulin resistance and hyperinsulinemia eventually lead to impaired glucose tolerance [36]. Except for maturity onset diabetes of the young (MODY), the mode of inheritance for type 2 diabetes mellitus is unclear.…”

Section: Type 2 Diabetes Mellitusmentioning

confidence: 99%

Classification, Pathophysiology, Diagnosis and Management of Diabetes Mellitus

Baynest¹

2015

J Diabetes Metab

264

250

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Diabetes Mellitus (DM) is a metabolic disorder characterized by the presence of chronic hyperglycemia either immune-mediated (Type 1 diabetes), insulin resistance (Type 2), gestational or others (environment, genetic defects, infections, and certain drugs). According to International Diabetes Federation Report of 2011 an estimated 366 million people had DM, by 2030 this number is estimated to almost around 552 million. There are different approaches to diagnose diabetes among individuals, The 1997 ADA recommendations for diagnosis of DM focus on fasting Plasma Glucose (FPG), while WHO focuses on Oral Glucose Tolerance Test (OGTT). This is importance for regular follow-up of diabetic patients with the health care provider is of great significance in averting any long term complications.

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“…TRO is an agonist of the peroxisome proliferator-activated receptor ␥ (PPAR␥) (Lehmann et al, 1995;Mahler and Adler, 1999) that sensitizes target cells to insulin, thereby improving the metabolic conditions associated with adult-onset diabetes. Although the precise mechanism of action of TRO is still not fully understood, the insulin-sensitizing effects of TRO are believed to be mediated through the activation of PPAR␥.…”

mentioning

confidence: 99%

Critical Role of c-Jun N-Terminal Protein Kinase Activation in Troglitazone-Induced Apoptosis of Human HepG2 Hepatoma Cells

Bae

Song²

2003

Mol Pharmacol

125

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The peroxisome proliferator-activated receptor agonist troglitazone (TRO) was used for treatment of non-insulin-dependent diabetes until its removal from the market because of its severe hepatotoxicity. However, the mechanism for its hepatotoxicity is still poorly understood. In this study, we investigated whether TRO caused cell death by altering signaling pathways associated with cell damage and survival in human hepatoma cells. Our data reveal that TRO caused time-and concentrationdependent apoptosis of HepG2 and Chang liver human hepatoma cells, as evidenced by DNA fragmentation and staining with Hoechst 33342. In contrast, 50 or 100 M rosiglitazone, a structural analog of TRO, did not cause apoptosis in these hepatoma cells. TRO activated both c-Jun N-terminal protein kinase (JNK) and p38 kinase about 5-fold between 0.5 and 8 h before they returned to control levels at 16 h in HepG2 cells. In contrast, TRO failed to activate the extracellular signal-regulated kinase. Furthermore, TRO increased the levels of proapoptotic proteins, Bad, Bax, release of cytochrome c, and cleavage of Bid in a time-dependent manner. The antiapoptotic Bcl-2 protein level decreased in hepatoma cells treated with TRO. Pretreatment of hepatoma cells with a selective JNK inhibitor, anthra[1,9-cd]pyrazol-6(2H)-one (SP600125), significantly reduced the rate of TRO-induced cell death, whereas 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole (SB203580), an inhibitor of p38 kinase, had little effect on apoptosis. Pretreatment with SP600125 also prevented JNK activation and c-Jun phosphorylation. In addition, rosiglitazone, which is not as toxic to hepatoma cells as TRO, did not stimulate JNK activity. Transfection of cDNA for the dominant-negative mutant JNK-KR (Lys3 Arg) or SEK1-KR (Lys3 Arg), an immediate upstream kinase of JNK, significantly reduced TRO-induced JNK activation and cell death rate. Furthermore, SP600125 pretreatment effectively prevented the TRO-mediated changes in Bad, Bax, Bid cleavage, and cytochrome c release. These data strongly suggest that hepatotoxic TRO causes apoptosis by activating the JNK-dependent cell death pathway accompanied by increased Bid cleavage and elevation of proapoptotic proteins.

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Type 2 Diabetes Mellitus: Update on Diagnosis, Pathophysiology, and Treatment

Cited by 133 publications

References 107 publications

One Week’s Treatment With the Long-Acting Glucagon-Like Peptide 1 Derivative Liraglutide (NN2211) Markedly Improves 24-h Glycemia and α- and β-Cell Function and Reduces Endogenous Glucose Release in Patients with Type 2 Diabetes

One Week’s Treatment With the Long-Acting Glucagon-Like Peptide 1 Derivative Liraglutide (NN2211) Markedly Improves 24-h Glycemia and α- and β-Cell Function and Reduces Endogenous Glucose Release in Patients with Type 2 Diabetes

Classification, Pathophysiology, Diagnosis and Management of Diabetes Mellitus

Critical Role of c-Jun N-Terminal Protein Kinase Activation in Troglitazone-Induced Apoptosis of Human HepG2 Hepatoma Cells

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