Diabetes mellitus affects virtually every organ system in the body and the degree of organ involvement depends on the duration and severity of the disease, and other co-morbidities. Gastrointestinal (GI) involvement can present with esophageal dysmotility, gastro-esophageal reflux disease (GERD), gastroparesis, enteropathy, non alcoholic fatty liver disease (NAFLD) and glycogenic hepatopathy. Severity of GERD is inversely related to glycemic control and management is with prokinetics and proton pump inhibitors. Diabetic gastroparesis manifests as early satiety, bloating, vomiting, abdominal pain and erratic glycemic control. Gastric emptying scintigraphy is considered the gold standard test for diagnosis. Management includes dietary modifications, maintaining euglycemia, prokinetics, endoscopic and surgical treatments. Diabetic enteropathy is also common and management involves glycemic control and symptomatic measures. NAFLD is considered a hepatic manifestation of metabolic syndrome and treatment is mainly lifestyle measures, with diabetes and dyslipidemia management when coexistent. Glycogenic hepatopathy is a manifestation of poorly controlled type 1 diabetes and is managed by prompt insulin treatment. Though GI complications of diabetes are relatively common, awareness about its manifestations and treatment options are low among physicians. Optimal management of GI complications is important for appropriate metabolic control of diabetes and improvement in quality of life of the patient. This review is an update on the GI complications of diabetes, their pathophysiology, diagnostic evaluation and management.

Human obesity is associated with insulin resistance, hyperinsulinemia, and a predisposition to hypertension and vascular disease, the origin of which may lie in impairment of endothelial function. We tested the effects of the thiazolidinedione rosiglitazone on blood pressure and endothelial function in insulin-resistant fatty Zucker rats, which display hypertension and abnormal endothelial cell function. We studied fatty Zucker rats given rosiglitazone maleate (50 micromol/kg diet; n = 8) for 9-12 weeks (treated fatty), untreated fatty rats (n = 8), and lean rats (n = 8) given diet alone. At the end of the study, systolic blood pressure was significantly higher in untreated fatty (147 +/- 5 mmHg) than in lean rats (125 +/- 2 mmHg; P < 0.05), but rosiglitazone treatment prevented the development of hypertension in fatty rats (123 +/- 1 mmHg). Fasting hyperinsulinemia in untreated fatty rats (28.7 +/- 6.0 ng/ml) was significantly lowered by rosiglitazone (7.0 +/- 1.4 ng/ml; P < 0.05 vs. untreated fatty), but remained significantly higher than the levels seen in lean rats (1.5 +/- 0.4 ng/ml; P < 0.01). Mesenteric arteries were studied in a myograph. Maximal acetylcholine chloride (1.1 micromol/l)-induced relaxation of norepinephrine hydrochloride (NE)-induced constriction was impaired in untreated fatty (62.4 +/- 3.4%) vs. lean (74.3 +/- 3.5%; P = 0.01) rats; this defect was partially prevented by rosiglitazone (66.5 +/- 3.0%; P = 0.01 vs. untreated fatty). Insulin (50 mU/l) significantly attenuated the contractile response to NE in lean rats (14.7 +/- 3.3%; P = 0.02); this vasodilator effect of insulin was absent in untreated fatty rats at concentrations of 50-5,000 mU/l, but was partially restored by rosiglitazone (9.7 +/- 2.5% attenuation; P = 0.02 vs. no insulin). Thus, rosiglitazone prevents the development of hypertension and partially protects against impaired endothelial function associated with insulin resistance. These latter effects may contribute to the drug's antihypertensive properties.

BRL 49653 (rosiglitazone) and troglitazone are thiazolidinedione insulin-sensitizing agents, which are undergoing clinical evaluation as treatments for NIDDM. Potential side effects of thiazolidinediones include edema and hemodilution. Although the underlying mechanisms are presently unclear, animal and human studies have demonstrated a vasodilator action of troglitazone, which could in theory cause fluid retention. This in vitro study compared the direct vasodilator effects of troglitazone and BRL 49653 in small arteries (n = 44) from human subcutaneous fat. In arterial rings with a functioning endothelium and preconstricted with norepinephrine (NE; 6 micromol/l), troglitazone (n = 22 vessels), but not BRL 49653 (1-100 micromol/l), caused a concentration-related relaxation (69.4 +/- 5.2% at 100 micromol/l; P < 0.01). In the presence of indomethacin (IM; 10 micromol/l; n = 12), this vasorelaxant effect of troglitazone was abolished (P < 0.01 vs. troglitazone alone) and replaced by enhanced vasoconstriction (58.5 +/- 39.5% over the NE baseline) similar in magnitude to that produced by troglitazone vehicle (ethanol) alone (n = 16; NS vs. ethanol vehicle). By contrast, BRL 49653 (100 micromol/l; n = 22) and an equivalent volume of ethanol alone (n = 12) caused similar degrees of vasoconstriction (18.7 +/- 14.6 and 22.5 +/- 8.0%, respectively; NS). In the presence of IM (10 micromol/l; n = 10), the vasoconstrictor effect of BRL 49653 was enhanced (41.5 +/- 14.4%), although not significantly (NS vs. BRL 49653 alone or ethanol alone). Additional studies in Wistar rat arteries showed a similar vasodilator effect of troglitazone that was not inhibited by L-NAME (100 micromol/l). The alpha-tocopherol moiety alone had no vasorelaxant effect at concentrations up to 300 micromol/l. Thus, in human arterial resistance vessels in vitro, BRL 49653 does not possess the direct, IM-sensitive vasorelaxant action of troglitazone. This vasodilation could, in theory, permit transmission of systemic pressure to the capillary bed.

1. Insulin resistance is associated with hypertension but the underlying mechanism is unclear. We tested the hypothesis that insulin-induced vasodilatation is impaired in insulin-resistant obese Zucker rats. We studied mesenteric artery (approximately 220 microns diameter) function before the development of hypertension in 3-month old obese Zucker rats and age-matched lean rats. 2. In vessels from lean rats, insulin at concentrations of 50, 500 and 5000 m-units/l attenuated the constriction in response to noradrenaline (50 m-units/l: 8 +/- 3%, P < 0.05; 500 m-units/l: 13 +/- 3%, P < 0.02; 5000 m-units/l: 13 +/- 2%, P < 0.02). 3. Vessels from obese rats failed to show any such response to insulin (2 +/- 6% increase in maximal tension with 5000 m-units/l; not significant), both in the presence and absence of L-arginine (3 mmol/l). 4. Vessels from obese rats showed slight but significant impairment in the vasodilator response to acetylcholine (5 x 10(-8)-10(-4) mol/l) (obese: 64.1 +/- 3.7% relaxation; lean: 77.3 +/- 3.7% relaxation; P < 0.05); however, relaxation in response to A23187 was not significantly different between the phenotypes (obese: 81.3 +/- 10.6% relaxation; lean: 79.1 +/- 9.7% relaxation; not significant). 5. Systolic blood pressure was not significantly different in lean (126 +/- 8 mmHg) and obese (127 +/- 7 mmHg) rats at the time of study (not significant). 6. We conclude that insulin-induced attenuation of noradrenaline-mediated vasoconstriction is impaired in the obese Zucker rat and that this defect precedes and therefore could contribute to the development of hypertension in this insulin-resistant model. The defect in insulin action could reside in the endothelial generation of nitric oxide, as endothelial function is also abnormal.

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