No abstract

Attempts at replicating physiological insulin secretion, as a means of restoring the normal metabolic milieu and thereby minimizing the risk of diabetic complications, has become an essential feature of insulin treatment. However, despite advances in the production, purification, formulation and methods of delivery of insulin which have occurred in recent years, this has met with limited success. The current advocacy of intensive insulin therapy regimens involving multiple daily subcutaneous injection places a heavy burden of compliance on patients and has prompted interest in developing alternative, less invasive routes of delivery. To date, attempts to exploit the nasal, oral, gastrointestinal and transdermal routes have been mainly unsuccessful. The respiratory tree, with a large surface area, offers the greatest potential for the delivery of polypeptide drugs and there is renewed interest in administrating insulin by the intrapulmonary route. Current pulmonary drug delivery systems include a variety of pressurized metered dose inhalers, dry powder inhalers, nebulizers and aqueous mist inhalers. Recent clinical studies suggest a possible role for inhaled insulin in fulfilling meal-related insulin requirements in persons with Type 1 and Type 2 diabetes. Most experience with inhaled insulin has been obtained using either dry powder formulation in the Nektar Pulmonary Inhaler/Exubera device (Nektar Therapeutics Inc., San Carlos, CA, Aventis, Bridgewater, NJ, Pfizer, NY) or a liquid aerosol formulation in the AERx Insulin Diabetes Management System (Aradigm Corp., Hayward, CA, NovoNordisk A/S, Copenhagen, Denmark). If long-term safety and efficacy is confirmed, inhalation may become the first non-subcutaneous route of insulin administration for widespread clinical use. Despite overwhelming interest and investment in administering insulin via the oral route, success is not expected in the short term. Attempts at utilizing the buccal mucosa and skin are also continuing. Pancreatic transplantation will remain limited to those patients receiving a kidney transplant and immunotherapy. Islet cell transplantation is at an early though encouraging stage following the availability of new less toxic immunosuppressive agents. True insulin independence will require further advances in the combined fields of cell biology and genetics to ensure freedom from both the need for lifelong administration of insulin and the complications of diabetes.

The standardization of methodology and the provision of age-related reference values have been addressed for the design of and interpretation of data from a multicentre neuropathy trial. Age-related reference values were generated from 120 healthy volunteers. Vibration perception thresholds (VPT) deteriorated significantly with age (p less than 0.001). Patients were selected on the basis of age-related abnormal VPT and peroneal motor nerve conduction velocity. They were assessed at the beginning and end of a placebo run-in period (baseline data). The coefficients of variation (CV%) for VPT at the medial malleolus (16.81 per cent, n = 316) and great toe (19.23 per cent, n = 313) were lower compared to results in healthy volunteers (29.7 per cent and 20.8 per cent, respectively, n = 49). The CV% for expiratory:inspiratory (E:I) ratio (4.82 per cent, n = 215), Valsalva manoeuvre (10.84 per cent, n = 249) and 30:15 ratio (7.73 per cent, n = 292) from patients corresponded to those recorded in volunteers (7.6 per cent, n = 45 11.0 per cent, n = 49 9.5 per cent, n = 48, respectively). Most patient values for VPT at the great toe fell beyond the 95 centile line for volunteers. E:I ratio for volunteers showed a more variable relationship with age, although patient values appeared to be located below the 5 centile line for volunteer data.

The effects of porcine glucose-dependent insulinotropic polypeptide given by continuous intravenous infusion in normal subjects (n = 6) and Type 2 (non-insulin-dependent) diabetic patients (n = 6) have been investigated. The subjects were studied on 2 separate days after overnight fasts. On each day 25 g of glucose was infused from 0-30 min plus an infusion of either porcine glucose-dependent insulinotropic polypeptide (0.75 pmol . kg-1 . min-1) or control solution. During the glucose-dependent insulinotropic polypeptide infusion plasma glucose values were reduced in normal subjects from 30-60 min (p less than 0.01) and in Type 2 diabetic patients at 45 and 60 min (p less than 0.05). In the normal subjects insulin concentrations were greater from 10-35 min (p less than 0.01) following glucose-dependent insulinotropic polypeptide infusion and peak values were increased by 123%. In the Type 2 diabetic patients following glucose-dependent insulinotropic polypeptide infusion insulin levels were increased from 4-40 min (p less than 0.01) but peak values were only increased by 27%. In the normal subjects C-peptide values were greater from 25-45 min (p less than 0.01) following glucose-dependent insulinotropic polypeptide infusion and peak C-peptide levels were increased by 82%. In the Type 2 diabetic patients following the glucose-dependent insulinotropic polypeptide infusion C-peptide levels were increased from 6-55 min (p less than 0.01) and peak values were increased by 20%. Plasma glucose-dependent insulinotropic polypeptide levels were within the physiological post prandial range during the glucose-dependent insulinotropic polypeptide infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract

The impact of improved glycaemic control on renal function in newly-presenting Type 2 (non-insulin-dependent) diabetic patients has not been adequately researched. Consequently, glomerular filtration rate and effective renal plasma flow and urinary albumin excretion rates were determined in 76 subjects (age (mean (SD)): 54 (9.5) years; 50 male) of an original cohort of 110 newly-presenting normotensive non-proteinuric Type 2 diabetic patients following 6 months treatment with diet alone (n = 42) or with oral hypoglycaemic agents (n = 34). Significant reductions were observed in (presentation vs 6 months): body mass index (p < 0.001); fasting plasma glucose (p < 0.001); glycated haemoglobin (HbA1) (p < 0.001); systolic blood pressure (p < 0.01); and diastolic blood pressure (p < 0.001). Glomerular filtration rate declined from 117 (22) to 112 (21) ml.min-1 (p < 0.01), with unchanged effective renal plasma flow (534 (123) vs 523 (113) ml.min-1) and filtration fraction (22.4 (3.0) vs 21.8 (3.4)%). Albumin excretion rate (median (range)) declined from 1.1 (0.1-34.7) to 0.5 (0.1-29.9) micrograms.min-1 (p < 0.01). Changes in glomerular filtration rate (delta values) were inversely correlated with presentation values (p < 0.001), and positive relationships were observed with delta effective renal plasma flow (p < 0.01), and delta glycated haemoglobin (p < 0.05). Type 2 diabetic patients with glomerular filtration rate values at presentation over 120 ml.min-1 demonstrated significant reduction in glomerular filtration rate (n = 31; p < 0.001), whilst those with original values less than 120 ml.min-1 remained unchanged (n = 45).(ABSTRACT TRUNCATED AT 250 WORDS)

The acute effects of iv somatostatin (SRIH; 100 micrograms/h) on the urinary flow (Uvol), effective renal plasma flow (RPF), and glomerular filtration rate (GFR) were compared with those of a control infusion of 0.15 M NaCl in nine insulin-dependent diabetic (IDD) patients of less than 10 yr disease duration and six normal subjects (NS). RPF and GFR were measured using a standard primed constant isotope infusion of [125I]iodohippurate and [51Cr]chromium EDTA. Uvol, RPF, and GFR were measured during 20-min clearance periods. During the NaCl infusion mean Uvol, RPF, and GFR were 14.1 +/- 0.2 (+/- SEM), 708 +/- 4, and 150 +/- 1 mL/min in the IDD group and 12.7 +/- 0.4, 568 +/- 5, and 110 +/- 2 mL/min in the NS group, respectively. In the IDD patients Uvol, RPF, and GFR decreased from 16.6 +/- 1.8, 670 +/- 30, 146 +/- 4 mL/min pre-SRIH to 9.2 +/- 1 (P less than 0.001), 553 +/- 25 (P less than 0.001), and 130 +/- 5 (P less than 0.001) mL/min, respectively, at 120 min during the SRIH infusion. Similarly, in the NS group mean Uvol, RPF, and GFR were 14.2 +/- 0.6, 552 +/- 15, and 112 +/- 5 mL/min pre-SRIH and decreased to 7.4 +/- 0.6 (P less than 0.001), 422 +/- 7 (P less than 0.001), and 93 +/- 3 (P less than 0.001) mL/min, respectively, after 120 min of the SRIH infusion. SRIH, therefore, had a profound effect on renal function in both IDD patients and NS, resulting in a reduction in RPF, GFR, and, as a consequence, Uvol.

No abstract