Neuropsychological function in older subjects with non-insulin-dependent diabetes mellitus.

Neuropsychological function was compared in three well-matched groups of subjects: Group 1, 20 diabetic patients with hypertension, mean age 69.1 +/- 4.8 years, 14 males and 6 females; Group 2, 20 normotensive diabetic patients, mean age 69.0 +/- 6.2 years, 14 males and 6 females; Group 3, 20 healthy community controls, mean age 68.1 +/- 4.5 years, 13 males and 7 females. There were no significant differences between the groups in education or estimated IQ using the NART (National Adult Reading Test). Groups 1 and 2 did not differ significantly in duration of diabetes (mean 10.6 and 9.5 years, respectively), or mean glycosylated haemoglobin, HbA1 (mean 9.8 and 10.6%, respectively), or mean blood glucose before and after testing. On a battery neuropsychological tests, sensitive to cognitive impairment in older subjects, analysis of covariance using estimated IQ as the covariate showed no significant differences between the groups on tests of recall, with (Brown-Peterson Test) and without (Kendrick Object Learning Test) interference, forward and backward digit span, concentration (serial subtraction), verbal fluency, immediate and delayed prose recall, digit symbol substitution or psychomotor speed (Kendrick Digit Copying Test). These results provide no support for an association between cognitive deficits and Type 2 diabetes mellitus in older subjects or for the view that such deficits may also be mediated by hypertension.

Body weight estimation of elderly patients by nomogram.

OBJECTIVE: To determine a safe and easy way to estimate body weight (BW) accurately in nonambulant elderly patients. DESIGN: An anthropometric study of ambulant patients. PARTICIPANTS: Two hundred eleven ambulant inpatients, 108 males and 103 females. SETTING: Inpatient departments of the University Department of Geriatric Medicine, Cardiff, Wales, UK. MEASUREMENTS: Skinfold thickness of chin, triceps, forearm, wrist, subscapular, sternal angle, waist, suprailiac, knee, and calf; circumference of arm, forearm, thigh and calf; body weight, chest girth, abdominal girth, upper limb length, leg length, and body weight. Measurements were carried out by means of Harpenden Skin-Fold Caliper, tape measure, and bathroom scale. RESULTS: Measured body weight in males was highly correlated with both arm circumference and chest girth. In females, measured body weight was highly correlated with waist skinfold thickness and thigh circumference. Nomograms for weight estimation in males and females were constructed from the regression equations for these measurements. CONCLUSIONS: Convenient estimation of body weight in nonambulant patients may be carried out using nomograms, which, themselves, may be used as progress sheets to assess the effect of dietary supplementation on body weight.

The dawn phenomenon and diabetes control in treated NIDDM and IDDM patients.

The effect of glycaemic control on the early morning plasma glucose rise, 'the dawn phenomenon', was assessed in two matching diabetic patient groups each comprising five NIDDM and two IDDM patients per group, who were otherwise considered to be in poor (HbA1 = 11.2 +/- 0.6%) or good (HbA1 = 7.6 +/- 0.2%) glycaemic control. Hourly plasma concentrations of glucose, insulin, glucagon, cortisol, and growth hormone were measured between 03.00 and 09.00 h. In all the poorly controlled diabetic patients the mean rise in plasma glucose between 06.00-08.00 and 03.00 h was greater than or equal to 1.0 mmol/l. In contrast, the plasma glucose increment was less than 1.0 mmol/l in the well controlled diabetics. The overnight mean insulin levels in the poor and well controlled patient groups were 19.3 +/- 0.5 and 25.0 +/- 0.6 mU/l (P less than 0.001) respectively. Glucagon, cortisol, and growth hormone levels in the early morning showed no significant differences between the two groups. The decline in plasma insulin from 03.00 to 08.00 h and mean cortisol level between 03.00 and 06.00 h were both significantly correlated with the increase in plasma glucose between 03.00 and 08.00 h. We concluded that an increase of 1.0 mmol/l or more in plasma glucose during the early morning is of clinical importance.

Early morning hyperglycaemia "dawn phenomenon" in non-insulin dependent diabetes mellitus (NIDDM): effects of cortisol suppression by metyrapone.

To assess the effect of metyrapone on the early morning plasma glucose (PG) rise, seven NIDDM patients were studied from 2400 to 0900 h on two separate occasions one week apart. During the control study nights, patients received conventional therapy only (diet plus sulphonylurea) whereas on treatment nights, patients received in addition 30 mg/kg metyrapone orally at 2400 h. The plasma glucose (PG) levels from 0530 to 0900 h were significantly higher during the control night than the corresponding values following metyrapone. The control mean PG concentrations increased continuously from a nadir 8.4 +/- 1.1 mmol/l at 0400 h to a maximum of 9.4 +/- 1.1 mmol/l at 0800 h (p less than 0.01). In contrast following metyrapone administration a continuous decline in the PG concentration was noted from 2400 to 0800 h. The plasma glucose levels fell from 9.0 +/- 1.2 at 0400 h to 7.7 +/- 1.0 mmol/l at 0800 h (p less than 0.05). The mean overnight cortisol levels were 167.2 +/- 13.2 and 55.9 +/- 6.4 nmol/l (p less than 0.001) during the control and treatment studies, respectively. The cortisol levels were significantly higher during the control study at all time points from 0400 to 0900 h. No significant changes in insulin, C-peptide, glucagon, GH or catecholamine levels were observed between the two study periods. We conclude that the physiologic early morning rise in plasma cortisol possibly contributes to the pathogenesis of the dawn phenomenon in NIDDM patients.

Early morning hyperglycemia in insulin-dependent diabetes: acute and sustained effects of cholinergic blockade.

Nocturnal release of GH has been shown to be related to the early morning rise in plasma glucose (PG) seen in insulin-dependent diabetes mellitus (IDDM). We have studied the effects of suppression of nocturnal GH release during a single night (acute study) and after nightly suppression for 1 week (chronic study). Changes in plasma glucose and counter-regulatory hormone concentrations were monitored in six IDDM patients during a constant overnight insulin infusion alone, after addition of the anticholinergic agent pirenzepine to cause acute GH suppression, and again on the seventh night of such treatment. In control experiments (infusion of insulin alone; 0.075 mU/kg.min) PG increased from (mean +/- SEM) 5.6 +/- 0.6 mmol/L at 2400 h to 11.1 +/- 1.3 mmol/L at 0900 h (P = 0.0024). Addition of pirenzepine (100 mg at 2200 h and again at 2400 h) in the acute study resulted in a PG change from 5.6 +/- 0.3 mmol/L at 2400 h to 8.4 +/- 1.4 mmol/L at 0900 h (P = 0.17). After pirenzepine administration at the same dose for 7 nights, PG increased from 4.7 +/- 0.6 mmol/L at 2400 h to 6.8 +/- 1.2 mmol/L at 0900 h (P = 0.11). Increases in PG during the study period were significantly less after chronic treatment than after acute treatment compared with changes on control nights. The nocturnal release of GH, which was demonstrated in all patients during the control nights, was suppressed in all patients during the acute study and in four of six patients during the chronic studies. We conclude that initial reduction of the early morning rise of PG in IDDM is associated with acute suppression of nocturnal GH release, and that the more significant sustained effect of anticholinergic GH suppression on the rise of PG may be associated with additional indirect effects on insulin clearance.

Early-morning hyperglycemia in IDDM. Acute effects of cholinergic blockade.

Growth hormone (GH) hypersecretion in insulin-dependent diabetes mellitus (IDDM) subjects has been shown to be causally related to early-morning hyperglycemia. We studied the effect of nocturnal GH suppression on acute glycemic control in six IDDM patients during a constant overnight insulin infusion (0.075 mU.kg-1.min-1). In control experiments (infusion of insulin alone), plasma glucose increased from 5.6 +/- 0.6 mM at 2400 to 11.1 +/- 1.3 mM at 0900 (P = .0024). When in addition the cholinergic muscarinic antagonist pirenzepine was given (100 mg at 2200 and again at 2400), plasma glucose increased from 5.6 +/- 0.3 mM at 2400 to 8.4 +/- 1.4 mM at 0900 (P greater than .05). The nocturnal surges of GH that were demonstrated in all patients during the control nights were suppressed during the treatment nights. There were no significant changes in insulin, cortisol, or epinephrine concentrations. Mean glucagon and norepinephrine concentrations. Mean glucagon and norepinephrine concentrations were reduced from 127 +/- 2.7 ng/L and 8.7 +/- 0.5 nM to 101 +/- 1.9 ng/L (P less than .001) and 3.5 +/- 0.2 nM (P less than .001) on control and treatment nights, respectively. Neither glucagon nor norepinephrine concentrations changed significantly between 2400 and 0900 on either control or treatment nights. We conclude that nocturnal GH suppression by pirenzepine during a constant low-rate insulin infusion is associated with an attenuation of the early-morning plasma glucose rise.

Renal haemodynamics during short-term angiotensin converting enzyme inhibition in normotensive normoalbuminuric insulin dependent diabetics.

Effective renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed in early insulin dependent diabetics (duration of diabetes less than 10 yr) during short term administration of angiotensin converting enzyme inhibitor. In a double blind randomized study, RPF and GFR were measured in normotensive normoalbuminuric (albumin excretion rate less than 20 micrograms/min) male IDDs before and after two weeks of Captopril 25 mg bd (n = 6) or placebo (n = 6). RPF and GFR were measured by means of a primed constant infusion of 125I iodohippurate and 51CR EDTA, respectively and corrected for 1.73m2 surface area. Supine blood pressure was measured throughout the study period. Mean (+/- SE) systolic and diastolic blood pressures were unchanged in both groups of subjects, being 124 +/- 5 mmHg and 78 +/- 4 mmHg before and 126 +/- 5 mm and 81 +/- 4 mm during Captopril and 121 +/- 6 mm and 79 +/- 4 mm before and 120 +/- 5 mm and 80 +/- 3 mm during placebo administration. RPF and GFR remained unchanged during Captopril administration, from 719 +/- 28 ml/min and 148 +/- 6 ml/min prior to and 721 +/- 26 ml/min and 149 +/- 6 ml/min during therapy. Similarly RPF and GFR were unchanged in the placebo treated group at 634 +/- 24 ml/min and 143 +/- 5 ml/min before end 630 +/- 28 ml/min and 140 +/- 7 ml/min after two weeks. Glycaemic control was unchanged in either group during the study period.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant DNA derived monomeric insulin analogue: comparison with soluble human insulin in normal subjects.

OBJECTIVE: To compare the rate of absorption from subcutaneous tissue and the resulting hypoglycaemic effect of iodine-125 labelled soluble human insulin and a monomeric insulin analogue derived by recombinant DNA technology. DESIGN: Single blind randomised comparison of equimolar doses of 125I labelled soluble human insulin and insulin analogue. SETTING: Study in normal people at a diabetes research unit and a university department of medical physics. SUBJECTS: Seven healthy male volunteers aged 20-39 not receiving any other drugs. INTERVENTIONS: After an overnight fast and a basal period of one hour two doses (0.05 and 0.1 U/kg) of 125I labelled soluble human insulin and insulin analogue were injected subcutaneously into the anterior abdominal wall on four separate days. END POINT: To find a fast acting insulin for meal related requirements in insulin dependent diabetics. MEASUREMENTS and main results--Residual radioactivity at the injection site was measured continuously for the first two hours after injection of the 125I labelled preparations and thereafter for five minutes simultaneously with blood sampling. Frequent venous blood samples were obtained over six hours for determination of plasma immunoreactive insulin, insulin analogue, glucose, and glucagon values. Time to 50% of initial radioactivity at the injection site for the insulin analogue compared with soluble insulin was 61 v 135 minutes (p less than 0.05) with 0.05 U/kg and 67 v 145 minutes (p less than 0.001) with 0.1 U/kg. Concentrations in plasma increased faster after the insulin analogue compared with soluble insulin, resulting in higher plasma concentrations between 10 and 150 minutes (0.001 less than p less than 0.05) after 0.05 U/kg and between 40 and 360 minutes (0.001 less than p less than 0.05) after 0.1 U/kg. The hypoglycaemic response to insulin analogue was a plasma glucose nadir at 60 minutes with both doses compared with 90 and 120 minutes with soluble insulin at 0.5 and 0.1 U/kg respectively. The response of glucagon substantiated the earlier and more dramatic hypoglycaemic effect with the insulin analogue. CONCLUSIONS: The much faster absorption from subcutaneous tissue of the disubstituted monomeric insulin analogue compared with soluble insulin suggests that the analogue may be a potential candidate for rapid insulin delivery after subcutaneous bolus injection.

Non-insulin-dependent diabetic patients (NIDDMs) do not demonstrate the dawn phenomenon at presentation.

A dawn rise of plasma glucose (PG) and/or insulin, the 'dawn phenomenon', has been commonly reported in treated diabetic patients and normal subjects. To evaluate the effect of treatment on this phenomenon in non-insulin-dependent diabetics (NIDDMs), PG, C peptide, immunoreactive insulin (IRI), growth hormone (GH), cortisol, epinephrine, and norepinephrine were measured hourly between 24.00 and 09.00 h in 17 newly diagnosed untreated NIDDMs (group 1). The study was repeated in 11 patients after a year of treatment (group 2). The PG levels did not change significantly at any time from 03.00 to 08.00 h in group 1 but increased continuously from 6.7 +/- 0.5 mmol/l at 04.00 h to 7.8 +/- 0.5 mmol/l at 08.00 h (P less than 0.01) in group 2. IRI and C peptide decreased significantly after 07.00 h in both groups. GH and catecholamine changes were similar in group 1 and group 2. Cortisol levels showed a nadir at 02.00 h and a peak after 07.00 h in both groups. Our results demonstrate no dawn rise of mean PG, IRI and C peptide in newly diagnosed untreated NIDDMs but a significant rise of PG in the early morning period in NIDDMs after a year of treatment with diet alone and diet plus sulphonylureas. Therefore other factors such as treatment and/or duration of the diabetes may play an important role in the pathogenesis of the dawn phenomenon.

Soluble and Lente human insulin mixtures in normal man.

The interaction between soluble (Actrapid HM) and Lente (Monotard HM) human insulin preparations was examined in normal subjects. Incremental plasma insulin levels were determined following the subcutaneous administration of 6 U of soluble insulin admixed with 0.14 ml soluble insulin diluting medium, or 0.14 ml Lente diluting medium and injected either immediately or 5 min after preparation. For comparison separate but simultaneous injections of soluble (6 U) and Lente insulin (14 U) were administered subcutaneously. All injection volumes were identical. The incremental insulin levels were significantly greater between 60 and 90 min (p less than 0.05-0.01) following the administration of soluble insulin admixed with its own medium compared to the soluble insulin/Lente medium admixtures injected immediately and 5 min after preparation. There was no difference, however, in the plasma insulin profiles between the two soluble insulin/Lente medium schedules. The separate simultaneous administration of soluble and Lente insulin resulted in significantly higher plasma insulin levels at 30 and 90 min (p less than 0.05) when compared to the admixture injected immediately after preparation and from 30-120 min (p less than 0.05-0.01) compared to the admixture injected after 5 min. The two soluble/Lente insulin admixtures achieved similar plasma insulin profiles. Therefore when soluble human insulin is admixed with Lente human insulin and administered by subcutaneous injection immediately after admixing there is a significant reduction in the plasma insulin levels during the first 90 min in contrast to when the two preparations are given simultaneously by separate injection. Delaying the injection of the admixture for 5 min results in significantly lower insulin levels up to 120 min. These differences are reflected in the hypoglycaemic responses observed.

Dawn phenomenon: its frequency in non-insulin-dependent diabetic patients on conventional therapy.

The frequency of the dawn phenomenon has been studied in non-insulin-dependent diabetic (NIDDM) patients while they continued with their conventional therapy. Plasma glucose (PG) and immunoreactive insulin (IRI) were estimated hourly from 0300 to 0900 h in 19 NIDDM patients; 9 patients were treated by diet alone (group 1), and 10 patients were treated by diet and oral hypoglycemic agents (group 2). The dawn rise of plasma glucose was demonstrated in 17 (89.5%) of the 19 patients with mean +/- SE plasma glucose at 0300 h of 7.0 +/- 0.5 mM and at 0800 h of 8.4 +/- 0.6 (P less than .01). IRI in all patients rose from 14.7 +/- 1.3 microU/ml at 0500 h to 18.1 +/- 1.8 microU/ml at 0700 h (P less than .05). The changes in IRI levels at any time from 0300 to 0800 h in groups 1 and 2 when considered separately were insignificant. Thus, the dawn phenomenon occurs commonly in NIDDM patients taking their conventional therapy.

Renal response to intravenous somatostatin in insulin-dependent diabetic patients and normal subjects.

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.

The metabolic response to glucagon and glucagon-(1-21)-peptide in normal subjects and non insulin dependent diabetics.

The metabolic effects of glucagon leading to hyperglycaemia are well recognised. However, the spasmolytic properties of glucagon have only relatively recently been utilised in clinical medicine. The marked hyperglycaemia accompanying the smooth muscle relaxant action of glucagon has led to the development of smaller peptides derived from glucagon which may retain the spasmolytic effects without the metabolic consequences. This study compares the metabolic and hormonal response to one such peptide, glucagon-(1-21)-peptide, with the parent peptide glucagon. The results demonstrate that glucagon-(1-21)-peptide has no metabolic effects comparable to glucagon. In normal subjects and non-insulin dependent diabetics, glucagon-(1-21)-peptide has no stimulatory effect on the pancreatic beta-cell.

Human, porcine and bovine ultralente insulin: subcutaneous administration in normal man.

Six normal subjects received subcutaneous human, porcine, and bovine ultralente insulin (0.30 U/kg) and diluent (control) in randomized order. Plasma glucose, C-peptide, and insulin were measured for 32 h after injection. From 10 h onward human ultralente produced significantly lower plasma glucose levels (p less than 0.05-0.01) compared to bovine ultralente. Porcine ultralente produced an intermediate hypoglycaemic response up to 16 h and was similar to the bovine insulin from 24-32 h. Estimated exogenous insulin concentration was higher (p less than 0.05-0.001) following human ultralente compared to bovine ultralente between 2 and 22 h after injection. Up to 24 h the porcine preparation led to intermediate insulin levels, but becoming identical to bovine ultralente from 28-32 h. Peak mean exogenous insulin values for human, porcine, and bovine ultralente were 0.054, 0.044, and 0.023 nmol/l at 14, 16, and 18 h, respectively, reaching 0.022, 0.013, and 0.013 nmol/l at 32 h. The different pharmacokinetic behaviour of human and bovine ultralente insulin must be considered when initiating treatment with human ultralente or transferring patients from bovine to human ultralente.

Effect of somatostatin on renal function.

Somatostatin has profound effects on both splanchnic and portal vascular beds. The effects of intravenous somatostatin (100 micrograms/h) on urinary volume, effective renal plasma flow, and glomerular filtration rate were compared with the effects of a control infusion of physiological saline in six normal subjects. Renal plasma flow and glomerular filtration rate were measured by primed constant isotope infusions of iodine-125 iodohippurate and chromium-51 edetic acid. Urinary volume, renal plasma flow, and glomerular filtration rate were measured during 20 minute clearance periods. During the control infusion urinary volume, renal plasma flow, and glomerular filtration rate remained essentially unchanged at 254 (SEM 3) ml/20 min, 568 (5) ml/min/1.73 m2, and 110 (2) ml/min/1.73 m2 respectively. From similar basal values the infusion of somatostatin led to a rapid decrease in all three variables. After 120 minutes of infusion of somatostatin urinary volume, renal plasma flow, and glomerular filtration rate were reduced to 148 (17) ml/20 min (p less than 0.01), 422 (7) ml/min/1.73 m2 (p less than 0.001), and 93 (3) ml/min/1.73 m2 (p less than 0.05) respectively. This effect on renal function should be borne in mind whenever somatostatin is used.

Possible new method to improve detection of diabetic retinopathy: Polaroid non-mydriatic retinal photography.

Two retinal cameras (Canon CR2 45NM and CR3 45NM) have recently become available and are capable of producing an instant colour photography of a 45 degree field of retina, including the macula and optic disc, without dilatation of the pupils being necessary. The ability of each camera to detect diabetic retinopathy was compared with that of doctors in diabetic clinics using ophthalmoscopy during busy clinic hours. The CR3 was found to be considerably superior to the CR2 in terms of quality of photograph because it can use a smaller pupil. Overall, the detection rate of the camera was more than four times higher than that of ophthalmoscopy through undilated pupils and more than twice as high as that of ophthalmoscopy through dilated pupils. Lesions missed by ophthalmoscopy but detected by the camera included soft exudates and circinate rings of hard exudates, sometimes encroaching on the macula. Though various aspects of this system of screening for diabetic retinopathy, in particular its ability to detect new retinal vessels, have not yet been assessed, the system may prove beneficial in the detection and monitoring of diabetic retinopathy.