Exogenous Insulin In Patients Research Articles

Abstract 368: Insulin Promotes Hypoxic Vascular Injury in Insulin Resistance

Clinical studies targeting aggressive lowering of blood glucose in type 2 diabetes (T2DM) by exogenous insulin failed to show cardiovascular protection, but paradoxically increased cardiovascular mortality. Previously, we demonstrated cerebrovascular insulin resistance (IR) and reduced mitochondria-mediated vasodilation in Zucker obese (ZO) rats with IR compared to lean (ZL) controls. Communication between endoplasmic reticula (ER) and mitochondria play a critical role in metabolic functioning and responses to hypoxia. Tethering of mitochondria to ER by mitofusin 2 (MFN2) creates Ca 2+ microdomains to aid inter-organelle communication. Overexpression of glucose regulated protein 78 kDa (GRP78), an ER chaperone and a marker of ER stress, is protective by preempting ER Ca 2+ leak. Our aim is to demonstrate the adverse impact of IR on ER-mitochondrial interactions. Levels of mitochondrial proteins (MFN2 and voltage dependent anionic channel or VDAC), ER stress marker (GRP78), and endothelial nitric oxide synthase (eNOS) were determined in cerebral arteries from ZO and ZL treated with vehicle or insulin under normoxic or hypoxia-reoxygenation (H-R) conditions. ZO arteries displayed decreased MFN2 and VDAC, elevated GRP78, and increased eNOS monomer/dimer ratio (eNOS uncoupling) at baseline. In ZL arteries, MFN2 and GRP78 proteins were increased under normoxic (1.2±0.1 and 0.97±0.27 respectively; p<0.05 versus vehicle) and decreased under H-R conditions (1.43±0.4 and 0.43±0.02 respectively; p<0.05 versus vehicle) by insulin. In contrast, in ZO arteries, MFN2 and GRP78 proteins were decreased under normoxic (0.69±0.1 and 0.71±0.01 respectively; p<0.05 versus vehicle) and increased under H-R conditions (1.76±0.12 and 1.4±0.07 respectively; p<0.05 versus vehicle) by insulin. Insulin decreased eNOS uncoupling under H-R versus normoxia in ZL, but increased it in ZO arteries. Thus, ZO arteries with IR display impaired mitochondria-ER communication at baseline which was further exacerbated by insulin under H-R leading to increased oxidative vascular injury. Our study provides a mechanistic basis for increased cardiovascular mortality following intensive glucose lowering therapy by high exogenous insulin in patients with IR and T2DM.

Effect of Insulin Versus Triple Oral Therapy on the Progression of Hepatic Steatosis in Type 2 Diabetes

BackgroundHyperinsulinemia has been associated with hepatic fat deposition and ensuing insulin resistance. It is unknown if treatment with exogenous insulin in patients with type 2 diabetes, who are most prone...

Beyond the Era of NPH Insulin—Long-Acting Insulin Analogs: Chemistry, Comparative Pharmacology, and Clinical Application

The new rDNA and DNA-derived "basal" insulin analogs, glargine and detemir, represent significant advancement in the treatment of diabetes compared with conventional NPH insulin. This review describes blood glucose homeostasis by insulin in people without diabetes and outlines the physiological application of exogenous insulin in patients with type 1 and type 2 diabetes. The requirements for optimal basal insulin treatment are discussed and the methods used in the evaluation of basal insulins are presented. An essential criterion in the development of an "ideal" basal insulin preparation is that the molecular modifications made to the human insulin molecule do not compromise safety. It is also necessary to obtain a clear understanding of the pharmacokinetic and pharmacodynamic characteristics of the two currently available basal insulin analogs. When comparing glargine and detemir, the different molar concentration ratios of the two insulin formulations should be considered along with the nonspecificity of assay systems used to determine insulin concentrations. However, euglycemic clamp studies in crossover study design provide a good basis for comparing the pharmacodynamic responses. When the latter is analyzed by results of intervention clinical trials, it is concluded that both glargine and detemir are superior to NPH in type 1 and type 2 diabetes. However, there is sufficient evidence to demonstrate that these two long-acting insulin analogs are different in both their pharmacokinetic and pharmacodynamic profiles. These differences should be taken into consideration when the individual analogs are introduced to provide basal insulin supplementation to optimize blood glucose control in patients with type 1 and type 2 diabetes as well. PubMed-Medline was searched for articles relating to pharmacokinetics and pharmacodynamics of glargine and detemir. Articles retrieved were reviewed and selected for inclusion if (1) the euglycemic clamp method was used with a duration >or=24 h, (2) a single subcutaneous dose of glargine/detemir was used, and (3) area under the curve for insulin concentrations or glucose infusion rates were calculated.

Suppression of endogenous insulin secretion by exogenous insulin in patients with insulinoma.

Previous studies have demonstrated that endogenous insulin secretion is not suppressed by exogenous insulin in patients with insulinoma. In this study we examined whether insulin secretion in insulinoma patients is suppressed by exogenous insulin during hypoglycaemia. Sixteen insulinoma patients (5 men and 11 women) and 10 normal subjects were studied. Hyperinsulinaemic glucose clamp studies were performed at both euglycaemia (4.5 mmol/l glucose) and hypoglycaemia (2.5 mmol/l glucose). In normal subjects, plasma C-peptide levels were suppressed by 66% during the euglycaemic hyperinsulinaemic clamps (P < 0.01). In contrast, in insulinoma patients, plasma C-peptide levels increased by 25% during the clamps (P < 0.05). In the hypoglycaemic hyperinsulinaemic clamps, plasma C-peptide levels were nearly completely (91%) suppressed in normal subjects and partially (39%) suppressed in patients with insulinoma (P < 0.01). The decrease in C-peptide levels during the hypoglycaemic clamps was > 30% in 12 (75%) of 16 insulinoma patients and > 50% in 8 (50%) patients. This study demonstrated that in patients with insulinoma, insulin secretion was not suppressed by exogenous insulin during euglycaemia but was suppressed during hypoglycaemia, although the degree of suppression was less than that in normal subjects. Our results suggest that the feedback regulation of insulin secretion by exogenous insulin is partially retained in patients with insulinoma.

Optimization Of Insulin Therapy In Patients With Type 2 Diabetes

ObjectiveTo analyze emerging trends in effective utilization of insulin in the treatment of type 2 diabetes. MethodsA systematic management plan and requirements for successful insulin therapy in patients with type 2 diabetes are outlined. ResultsThe key to successful management of type 2 diabetes with insulin therapy is the use of adequate amounts of insulin and a bolus-to-basal insulin ratio of 1:1. Patient education about the progressive nature of the disease and the importance of self-monitoring of blood glucose is essential. The most effective method of sustaining normal blood glucose levels is to mimic the physiologic response to intake of food and thereby control postprandial glycemic excursions. Rapid-acting insulin lispro is useful in this effort. In the development of effective insulin regimens, one option is use of an insulin sensitizer in combination with bedtime NPH insulin. ConclusionBecause of deteriorating beta cell function, insulin deficiency results and usually necessitates administration of exogenous insulin in patients with type 2 diabetes. The goal of insulin treatment of type 2 diabetes is to achieve near-normal glycemic control. The insulin secretory defect progresses over time; thus, therapy must be continually matched to the underlying pathophysiologic defects. (Endocr Pract. 2000;6:93-97)

The current state of pancreas transplantation.

The first pancreas transplant in 1966 demonstrated that a pancreas allograft could reestablish euglycemia independent of exogenous insulin in patients with type 1 diabetes mellitus. Early outcomes were poor, and application of the procedure was limited. In the 1980s, innovations in immunosuppression therapy and surgical management of pancreatic exocrine secretions combined with careful candidate selection resulted in dramatic improvements in patient and graft survival. In the 1990s, the incorporation of additional new anti-rejection agents into immunosuppression protocols resulted in a further decrease in the incidence of acute rejection, affording more freedom in surgical management of exocrine drainage. The vision for the future of transplantation for the treatment of diabetes is focused on the percutaneous infusion of pancreatic islets, thus eliminating the need for surgical revascularization of a pancreas allograft, yet reestablishing regulation of glucose metabolism.

Effect of insulin treatment on circulating islet amyloid polypeptide in patients with NIDDM.

The objective was to evaluate the effect of insulin treatment on circulating islet amyloid polypeptide (IAPP). Twelve patients with NIDDM and secondary failure were studied on oral agents and then switched to insulin treatment. Fasting and postprandial IAPP concentrations were measured on oral treatment and on insulin treatment. In 5 of the patients no postprandial concentrations were determined. In the 7 patients who were investigated both fasting and postprandially the fasting IAPP concentration was 6.5 +/- 1.2 pmol l(-1) (mean +/- SEM) during oral treatment with a rise to 13.5 +/- 3.1 90 min after breakfast (p = 0.028). On insulin treatment HbA1c decreased from 8.6 +/- 0.5 to 7.5 +/- 0.4% (p< 0.03) and plasma C-peptide concentration was significantly lowered (p< 0.01). There was a close correlation using simple regression between the per cent change of IAPP concentration and the per cent change of C-peptide concentration during this period (r = 0.88; p< 0.01). In the total patient material of 12 patients there was a significant correlation using simple regression analysis between per cent change of IAPP concentration and per cent change of C-peptide concentration using all 48 measurements available (r = 0.58: p< 0.001). These data suggest that secretion of IAPP is lowered when endogenous insulin secretion is lowered by administration of exogenous insulin in patients with NIDDM. Thus, if IAPP secretion has a pathogenetic role in the development of beta cell failure in NIDDM, insulin treatment might delay this deterioration.