Showing papers in "Diabetologia in 1990"

Elevated plasma endothelin in patients with diabetes mellitus.

Abstract: Plasma concentrations of endothelin, a vasoconstrictor peptide released from vascular endothelial cells, have been measured by radioimmunoassay in 100 patients with diabetes mellitus and 19 healthy subjects. The plasma immunoreactive-endothelin concentrations were found to be greatly raised in the patients with diabetes (1,880±120 fmol/l, mean±SEM) compared with the healthy subjects (540±50 fmol/l, p<0.005). The elevation of immunoreactive-endothelin could not be explained by secondary changes in blood pressure or renal disease and did not correlate with the presence of diabetic retinopathy, duration of diabetes mellitus, fasting blood glucose or serum fructosamine. Fast protein liquid chromatographic analysis of the diabetic plasma immunoreactive-endothelin showed three forms, one in a very big molecular weight position, one intermediate and one in the position of endothelin-1 itself. No material appeared in the positions of endothelin-2 and 3. Chromatographic analysis of normal plasma showed only the big molecular weight peak while material in the endothelin-1,2 or 3 positions was below detection. The elevation of endothelin in diabetic patients may be a marker of, and further exacerbate, their vascular disease.

Hyperglycaemia slows gastric emptying in type 1 (insulin-dependent) diabetes mellitus.

Abstract: In 10 patients with Type 1 (insulin-dependent) diabetes mellitus gastric emptying of a digestible solid and liquid meal was measured during euglycaemia (blood glucose concentration 4–8 mmol/l) and during hyperglycaemia (blood glucose concentration 16–20 mmol/l). Gastric emptying was studied with a scintigraphic technique and blood glucose concentrations were stabilised using a modified glucose clamp. Patients were also evaluated for gastrointestinal symptoms, autonomic nerve function and glycaemic control. When compared to euglycaemia, the duration of the lag phase before any of the solid meal emptied from the stomach (p = 0.032), the percentage of the solid meal remaining in the stomach at 100 min (p = 0.032) and the 50% emptying time for the solid meal (p = 0.032) increased during hyperglycaemia. The 50% emptying time for the liquid meal (p = 0.042) was also prolonged during the period of hyperglycaemia. These results demonstrate that the rate of gastric emptying in Type 1 diabetes is affected by the blood glucose concentration.

Traditional plant treatments for diabetes. Studies in normal and streptozotocin diabetic mice

Abstract: The effects on glucose homeostasis of eleven plants used as traditional treatments for diabetes mellitus were evaluated in normal and streptozotocin diabetic mice. Dried leaves of agrimony (Agrimonia eupatoria), alfalfa (Medicago saliva), blackberry (Rubus fructicosus), celandine (Chelidonium majus), eucalyptus (Eucalyptus globulus), lady's mantle (Alchemilla vulgaris), and lily of the valley (Convallaria majalis); seeds of coriander (Coriandrum sativum); dried berries of juniper (Juniperus communis); bulbs of garlic (Allium sativum) and roots of liquorice (Glycyrhizza glabra) were studied. Each plant material was supplied in the diet (6.25% by weight) and some plants were additionally supplied as decoctions or infusions (1 g/400 ml) in place of drinking water to coincide with the traditional method of preparation. Food and fluid intake, body weight gain, plasma glucose and insulin concentrations in normal mice were not altered by 12 days of treatment with any of the plants. After administration of streptozotocin (200 mg/kg i.p.) on day 12 the development of hyperphagia, polydipsia, body weight loss, hyperglycaemia and hypoinsulinaemia were not affected by blackberry, celandine, lady's mantle or lily of the valley. Garlic and liquorice reduced the hyperphagia and polydipsia but did not significantly alter the hyperglycaemia or hypoinsulinaemia. Treatment with agrimony, alfalfa, coriander, eucalyptus and juniper reduced the level of hyperglycaemia during the development of streptozotocin diabetes. This was associated with reduced polydipsia (except coriander) and a reduced rate of body weight loss (except agrimony). Alfalfa initially countered the hypoinsulinaemic effect of streptozotocin, but the other treatments did not affect the fall in plasma insulin. The results suggest that certain traditional plant treatments for diabetes, namely agrimony, alfalfa, coriander, eucalyptus and juniper, can retard the development of streptozotocin diabetes in mice.

Familial predisposition to renal disease in two generations of Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus.

Abstract: We studied the occurrence of renal disease by measuring serum creatinine and urine protein concentrations in the diabetic members of 316 Pima Indian families with Type 2 (non-insulin-dependent) diabetes in two successive generations to determine if diabetic renal disease aggregates in families. After adjustment for sex and other risk factors, proteinuria occurred among 14.3% of the diabetic offspring if neither parent had proteinuria, 22.9% if at least one diabetic parent had proteinuria, and 45.9% if both parents had diabetes and proteinuria. Among male offspring, an elevated serum creatinine concentration (≥177 μmol/l) was present in 11.7% if the parent had an elevated creatinine and in 1.5% if the parent did not. Thus, proteinuria and high serum creatinine aggregated in diabetic families, suggesting that susceptibility to renal disease is inherited independently of diabetes.

Magnesium and glucose homeostasis

Abstract: Magnesium is an important ion in all living cells being a cofactor of many enzymes, especially those utilising high energy phosphate bounds. The relationship between insulin and magnesium has been recently studied. In particular it has been shown that magnesium plays the role of a second messenger for insulin action; on the other hand, insulin itself has been demonstrated to be an important regulatory factor of intracellular magnesium accumulation. Conditions associated with insulin resistance, such as hypertension or aging, are also associated with low intracellular magnesium contents. In diabetes mellitus, it is suggested that low intracellular magnesium levels result from both increased urinary losses and insulin resistance. The extent to which such a low intracellular magnesium content contributes to the development of macro- and microangiopathy remains to be established. A reduced intracellular magnesium content might contribute to the impaired insulin response and action which occurs in Type 2 (non-insulin-dependent) diabetes mellitus. Chronic magnesium supplementation can contribute to an improvement in both islet Beta-cell response and insulin action in non-insulin-dependent diabetic subjects.

The relationships of concentrations of insulin, intact proinsulin and 32-33 split proinsulin with cardiovascular risk factors in type 2 (non-insulin-dependent) diabetic subjects.

Abstract: Standard radioimmunoassay for insulin may substantially overestimate levels of insulin because of cross-reaction with other insulin-like molecules. We have measured concentrations of insulin, intact proinsulin and 32–33 split proinsulin using two-site monoclonal antibody based immunoradiometric assays, and of insulin by a standard radioimmunoassay (“immunoreactive insulin”) in 51 Type 2 (noninsulin-dependent) diabetic subjects in the fasting state. The relationships of these concentrations were sought with those of total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride, plasminogen activator inhibitor, blood pressure, and indices of body fat distribution. Significant relationships were apparent between concentrations of “immunoreactive insulin” as measured by standard radioimmunoassay and triglyceride (r s=0.42, p<0.001), total cholesterol (r s=0.25, p=0.038), high density lipoprotein cholesterol (r s=−0.30, p=0.018) and body mass index (r s=0.30, p=0.017), but only the relationships with triglyceride (r s=0.36, p=0.006) and body mass index (r s=0.26, p=0.034) remained significant when concentrations of immunoradiometrically measured insulin were employed. Concentrations of 32—33 split proinsulin, which comprises the major insulin-like molecule in these subjects, correlated positively with triglyceride (r s=0.33, p=0.009), total cholesterol (r s=0.23, p=0.050), and plasminogen activator inhibitor (r s=0.26, p=0.049), and negatively with high density lipoprotein cholesterol (r s=−0.29, p=0.021). Concentrations of “immunoreactive insulin” and immunoradiometric assay insulin showed significant positive correlaion with both systolic (r s=0.24, p=0.044 and r s=0.29, p=0.020 respectively), and diastolic blood pressure (r s=0.48, p<0.001 and n=0.42, p=0.001 respectively), while those of intact proinsulin and 32–33 split proinsulin correlated only with diastolic blood pressure (r s=0.33, p=0.009 and r s=0.31, p=0.014 respectively). Using multiple regression analysis, and including age, sex, race and body mass index in the analyses, concentrations of intact proinsulin and 32–33 split proinsulin, but not immunoradiometric assay insulin, were significantly related to diastolic blood pressure. When all three molecules were incorporated into a single model, only 32–33 split proinsulin was related to diastolic blood pressure (F-change=6.91, [5,43 degrees of freedom]; p=0.012). Thus, high concentrations of insulin-like molecules are associated with changes in recognised cardiovascular risk factor in patients with Type 2 (non-insulin-dependent) diabetes mellitus.

A prospective study of mortality among middle-aged diabetic patients (the London cohort of the WHO multinational study of vascular disease in diabetics). I, Causes and death rates

Abstract: Potential risk factors have been examined for association with mortality over a 10–12 year follow-up of the patients of the London Cohort of the WHO Multinational Study of Vascular Disease in Diabetics (aged 35–54 year in at entry to the study). Proteinuria has the strongest association with all-cause mortality in univariate analysis being significant in patients of both sexes with Type 2 (non-insulin-dependent) diabetes mellitus and in women with Type 1 (insulin-dependent) diabetes mellitus; both systolic blood pressure (men) and hypertension (both sexes) (as a categorical variable) are significant in Type 1 diabetes. Hypertension is also significantly associated with all-cause mortality in multivariate analysis in both sexes with Type 1 diabetes as proteinuria is in women with Type 2 diabetes. There is an unexpected negative association between plasma creatinine and all-cause mortality in men with Type 2 diabetes. Systolic blood pressure and hypertension are also significantly linked with cardiovascular mortality in Type 1 diabetes, hypertension having an estimated relative risk of 18.6 in multivariate analysis. Serum cholesterol and proteinuria showed the strongest associations with cardiovascular mortality in Type 2 diabetes. Proteinuria is associated with non-cardiovascular mortality in both types of diabetes in univariate but not multivariate analysis. In multivariate analysis hypertension (Type 1 diabetes) and diabetes duration (Type 2 diabetes) are associated with non-cardiovascular mortality. Hypertension and proteinuria have the most consistent associations with mortality in the different analyses with the effect of hypertension appearing stronger in Type 1 diabetes and proteinuria in Type 2 diabetes. Some other proven risk factors in non-diabetic populations had inconstant or absent associations in this group: other, as yet undefined, factors may be important in diabetes.

Relationship between haemoglobin A1C in early type 1 (insulin-dependent) diabetic pregnancy and the occurrence of spontaneous abortion and fetal malformation in Sweden.

Abstract: This prospective nationwide study examined the relationship between diabetic control in early pregnancy as assessed by HbA1C and the incidence of spontaneous abortion and fetal malformation. HbA1C and plasma C-peptide were determined in 532 women with Type 1 (insulin-dependent) diabetes mellitus, corresponding to approximately 80% of all the diabetic pregnancies in the country during the study period 1982–1985, and 222 non-diabetic control women. Median gestational week for sampling was 9.0 in the Type 1 diabetic and 10.0 in the control group. The median value of HbA1C was 7.7% in the diabetic and 5.3% in the control group (p 10.1% equal to 8 SD above the normal mean control value, was significantly associated with the occurrence of spontaneous abortion (p<0.001) and malformation (p<0.01). Discriminant analysis revealed that after correction had been made for the significant value of HbA1C to predict the occurrence of spontaneous abortion and malformation, no further predictive power was displayed by measurable plasma C-peptide, maternal age or duration of diabetes or presence of diabetic microangiopathy. We conclude that poor metabolic control in early pregnancy contributes to an increased risk of both spontaneous abortion and fetal malformation.

Permanent neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man.

Abstract: Seventeen Type 1 (insulin-dependent) diabetic patients with a history of recurrent and severe hypoglycaemia and Type 1 diabetic patients with no severe hypoglycaemia were compared as regarded performances in tests of neuropsychological functioning. To test the hypothesis that recurrent severe hypoglycaemia gives rise to permanent cognitive impairment, the study group was selected among those patients who had met with repeated attacks over the last three years or more as identified by a questionnaire among almost 600 insulin-treated diabetic patients. The comparison group without known severe reactions were comparable to the study group with respect to type of diabetes, sex, age, age at onset, duration of diabetes, socio-economic parameters, and prevalence of neuropathy and retinopathy. The results indicate that Type 1 diabetic patients with recurrent severe hypoglycaemia scored lower than those without severe hypoglycaemia in tests of motor ability, short-term and associative memory and visuospatial tasks assessing ability in general problem-solving. Type 1 diabetic patients with severe hypoglycaemia also displayed a higher frequency of perspective reversals suggesting frontal-lobe involvement. These data can be interpreted in two ways. One interpretation implies that the cognitive impairment of Type 1 diabetic patients with severe hypoglycaemia reflects a selection factor, the other that recurrent episodes of severe hypoglycaemia result in permanent cognitive impairment.

Unexplained variability of glycated haemoglobin in non-diabetic subjects not related to glycaemia.

Abstract: We have studied levels of glycated haemoglobin in a sample of 223 people aged over 40 years without known diabetes mellitus screened in a community study. Each had a glucose tolerance test and glycated haemoglobin measured by four methods — agar gel electrophoresis with and without removal of Schiff base, affinity chromatography and isoelectric focusing. The correlation coefficients between 2 h blood glucose and levels of glycated haemoglobin were between 0.43 and 0.64. This poor correlation was not explained on the basis of assay or biological variability of either 2 h blood glucose or glycated haemoglobin. Multiple regression analysis showed that other assays of glycated haemoglobin contributed to the variance of any single glycated haemoglobin value by 0.1%–52.9% (median 12.8%) compared to the variance of 18.6%–41.4% (median 30.8%) explained by 2 h blood glucose alone, suggesting that in a non-diabetic population, the degree of glucose intolerance may explain only one third of the variance of glycated haemoglobin levels, but other factors operate to produce consistent changes in levels of glycated haemoglobin. Investigation of 42 subjects with consistently high (20 subjects) or low (22 subjects) levels of glycated haemoglobin relative to their 2 h blood glucose level showed no difference in age, gender, body mass index, haemoglobin levels or smoking, although 50% of low glycators had impaired glucose tolerance. Neither ambient bloodglucose levels, as estimated on two five-point blood-glucose profiles, nor dietary intake of carbohydrate, starch, sugars, fibre or alcohol, explained the difference between high and low glycators. The determinants of the consistent interindividual differences in levels of glycated haemoglobin in nondiabetic subjects remain to be determined.

Expression of insulin regulatable glucose transporters in skeletal muscle from Type 2 (non-insulin-dependent) diabetic patients

Abstract: A prominent feature of Type 2 (non-insulin-dependent) diabetes mellitus is the inability of insulin to appropiately increase the transport of glucose into target tissue. In adipocytes from individuals with Type 2 diabetes, insulin resistance has been shown to be associated with a depletion of glucose transporters. Similarly, streptozotocin induced diabetes causes a diminished expression of the insulin regulatable glucose transporter in rat adipocytes. The expression of this glucose transporter isoform has not yet been investigated in muscle tissue from patients with Type 2 diabetes. We have measured the content of the insulin regulatable glucose transporter in a vesicular fraction isolated from muscle biopsies from fasting individuals with Type 2 diabetes and control subjects, and we found that the number of the insulin regulatable glucose transporters expressed in skeletal muscle was unaffected by Type 2 diabetes (0.208 vs 0.205, arbitrary units, p>0.5, control subjects and diabetic patients). Thus, the decreased glucose disposal in Type 2 diabetes is not associated with a diminished number of insulin regulatable glucose transporters.

On the determination of basal glucose production rate in patients with type 2 (non-insulin-dependent) diabetes mellitus using primed-continuous 3-3H-glucose infusion.

Abstract: Using primed-continuous 3-3H-glucose infusion, basal glucose production rate has been reported to be 140% higher than normal or almost normal in hyperglycaemic patients with Type 2 (non-insulin-dependent) diabetes mellitus. To determine whether these markedly different results could be due to the mode of priming: fixed or adjusted, or the mode of calculation: steady state or non-steady state equations, we studied 11 patients with Type 2 diabetes (fasting plasma glucose 8–20 mmol/l). For 6 h 3-3H-glucose (0.40 μCi/min) was infused preceded by a priming dose of 40 μCi (fixed priming), or 40 μCi · plasma glucose (mmol/l)·5−1 (adjusted priming). In diabetic patients the plasma glucose concentration was not constant but declined 0.52±0.07 mmol·l−1· h−1. Furthermore, the rate of fall was correlated to the fasting plasma glucose concentration (r=0.90, p<0.01). Thus, the fasting state was not a steady state condition. Using adjusted priming a constant tracer steady state level was obtained within 60 min. In contrast, using fixed priming tracer steady state was not reached within 6 h. The initial tracer level was far below, and increased in time towards the steady state level observed after adjusted priming. Consequently, using Steele's equations after fixed priming, glucose production rates calculated after 90–120 min were overestimated in proportion to fasting hyperglycaemia. In conclusion: The fasting state in patients with Type 2 diabetes is not a steady state condition. Adjusted priming seems most appropriate in Type 2 diabetes. By estimating glucose production 2 h after fixed priming or assuming steady state conditions, most previous studies may have overestimated basal glucose production in Type 2 diabetes in proportion to fasting hyperglycaemia.

Microalbuminuria predicts the development of serum lipoprotein abnormalities favouring atherogenesis in newly diagnosed type 2 (non-insulin-dependent) diabetic patients

Abstract: We studied the relationship of slight albuminuria (microalbuminuria) to serum lipid and lipoproteins in a representative group of middle-aged Type 2 (non-insulin-dependent) diabetic patients. A random sample of non-diabetic control subjects was also examined. Diabetic patients had both at diagnosis and after five years higher total, LDL- and VLDL-triglyceride levels and higher VLDL-cholesterol, but lower HDL-cholesterol levels than non-diabetic subjects. No consistent difference was found in LDL-cholesterol levels between diabetic and non-diabetic subjects. The prevalence of microalbuminuria (>35 mg/24 h) remained about the same in diabetic patients at both examinations (19–20%). The diabetic patients with persistent microalbuminuria were slightly hyperglycaemic and they tended to have lower creatinine clearance at the 5-year examination than those without persistent microalbuminuria. There were no differences in the blood pressure levels or the occurrence of hypertension between the diabetic groups with and without microalbuminuria. At the baseline examination, no differences were seen in serum lipids and lipoproteins between diabetic patients with and without microalbuminuria. In patients with persistent microalbuminuria. a statistically significant increase in VLDL-cholesterol (p<0.05) and VLDL- and LDL-triglyceride levels (p<0.05) and a decrease in HDL-cholesterol level (p<0.05) was seen at the 5-year follow-up. These changes could not be explained by age, sex, body mass index or HbA1. In conclusion, persistent microalbuminuria predicts and aggravates abnormalities in lipoprotein composition and a decrease in HDL-cholesterol in patients with Type 2 diabetes mellitus. The excess cardiovascular morbidity and mortality in diabetic patients with increased albuminuria may, in part, be explained by these lipoprotein abnormalities.

A multicentre trial of the aldose-reductase inhibitor, tolrestat, in patients with symptomatic diabetic neuropathy.

Abstract: The effects of the aldose-reductase inhibitor, tolrestat, on chronic symptomatic diabetic sensorimotor neuropathy were studied during a placebo-controlled, randomised, 52-week multicentre trial. Of the four tolrestat doses investigated, only the highest dose group, 200 mg once daily, showed subjective and objective benefit over baseline and placebo, and further analyses are confined to this group (n=112) and placebo (n=107). Painful and paraesthetic symptoms were analysed separately: improvement in paraesthetic symptoms were seen at one year (p=0.04), though painful symptoms improved on both placebo and active therapies. Significant improvement in both tibial and peroneal motor nerve conduction velocities were seen at 52 weeks. Tolrestat 200 mg once daily was significantly better than placebo in producing concordant improvements in both motor nerve conduction velocities and paraesthetic symptom scores at 24 weeks (p=0.01), 42 weeks (p=0.01) and 52 weeks (p=0.02). Long-term benefit [condordant improvement at 24 weeks maintained until 52 weeks] was seen in 28% of treated patients compared to 5% on placebo (p=0.001). It is concluded that some sustained improvement in symptomatic diabetic neuropathy may be obtained following aldose-reductase inhibition with tolrestat 200 mg once daily.

A search for the presence of the enteroviral capsid protein VP1 in pancreases of patients with Type 1 (insulin-dependent) diabetes and pancreases and hearts of infants who died of coxsackieviral myocarditis

Abstract: Using an antiserum raised to a recombinant coxsackie virus B3 capsid protein, VP1, an immunocytochemical technique was developed which was capable of detecting the presence of all coxsackie B viruses in formalin fixed paraffin embedded infected tissue culture cells. This technique was tested on autopsy heart and pancreas from 21 patients who were thought to have died of acute coxsackievirus B myocarditis. Cardiac myocytes were positive for the VP1 protein in 12 of 20 cases where the heart was available for study. Insulitis was present in the pancreas in seven of these cases and in all seven islet endocrine cells containing VP1 were found. VP1 was only rarely found in exocrine pancreas. In heart and pancreas, cells shown to contain VP1 usually showed signs of necrosis. Autopsy pancreases from 88 patients who had died at clinical presentation of Type 1 (insulin-dependent) diabetes mellitus showed no evidence of the presence of VP1. The continuing destruction of insulin-secreting B cells seen at the time of death in the diabetic pancreas is unlikely to be due to a direct cytopathic effect of a coxsackie B virus. However, this study does not exclude the possibility that a persistent infection of B cells by a defective enterovirus may result in their destruction by an autoimmune mechanism.

Evidence for lactate production by human adipose tissue in vivo.

Abstract: Microdialysis of the abdominal subcutaneous tissue was performed in seven healthy normal weight subjects after an overnight fast and also after oral ingestion of 100 g glucose. The lactate concentration in the interstitial water was compared with that in the venous and arterialized plasma from the cubital veins. In the postabsorptive state the lactate concentration in the subcutaneous tissue (1128±72 μmol/l, mean±SEM) was significantly higher (p<0.01) than that in both arterialized (722±72 μmol/l) and venous plasma (798±41 μmol/l). The oral glucose load further increased the lactate level in the subcutaneous tissue throughout the observation period of 2 h. The kinetics for the increase in the lactate concentration was not apparently different in blood or tissue. The highest lactate levels were 1798±173 umol/l in the subcutaneous tissue and 1199±150 μmol/l and 1275±123 μmol/l in arterialized and venous plasma, respectively. It is concluded that abdominal adipose tissue produces lactate both in the fasting state and after an oral glucose load. The data emphasize the importance of the adipose tissue as a significant source of lactate production in the body.

Expression of reg protein in rat regenerating islets and its co-localization with insulin in the Beta cell secretory granules

Abstract: Regenerating islets can be induced by the administration of poly(ADP-ribose) synthetase inhibitors to 90% depancreatized rats. In screening a regenerating islet-derived cDNA library, we previously isolated a novel gene. reg (regenerating gene), which encodes a 165-amino acid protein with a 21-amino acid signal sequence. In the present study, we have examined the expression and localization of reg protein in the regenerating islets by immunocytochemical techniques using a monoclonal antibody against a recombinant rat reg protein of 144 amino acids without the signal sequence. Light microscopy examination showed strong immunoreactivity for reg protein in the regenerating islets of the rats at two weeks and two months after 90% pancreatectomy, whereas reg protein was almost undetectable in normal rat islets or in the islets of the rats one year after the pancreatectomy. Almost all the reg protein-positive cells were stained for insulin. By applying the immunogold technique at the ultrastructural level, it was demonstrated that both reg protein and insulin occur in the central granular core of the regenerating Beta cell secretory granules. These results suggest that reg protein is synthesized in and secreted from the regenerating Beta cells and that its expression is closely associated with Beta-cell regeneration.

Prevalence of hypertension in type 1 (insulin-dependent) diabetes mellitus

Abstract: The prevalence of hypertension in a representative sample (n = 10202) of the Danish general population aged 16-59 years was assessed to 4.4% based on three blood pressure readings. In Type 1 (insulin-dependent) diabetic patients of similar age (n = 1703) the prevalence was determined in a similar way to 14.7% (p less than 0.00001). The excess prevalence in Type 1 diabetic patients was due to hypertension in patients with incipient and clinical nephropathy as the prevalence of hypertension among diabetic patients with normal urinary albumin excretion (essential hypertension) was 3.9%, similar to that observed in the general population. The patients with Type 1 diabetes and essential hypertension had higher systolic (146 +/- 19 vs 133 +/- 18 mm Hg, p less than 0.00001) and diastolic blood pressure (87 +/- 12 vs 79 +/- 7 mm Hg, p less than 0.00001), but less changes in the eye background than patients with incipient nephropathy (urinary albumin excretion 30-300 mg/24 h) (p less than 0.03), indicating that the two groups were also different with respect to other microangiopathic lesions. Patients with essential hypertension were defined as having a normal urinary albumin excretion before and during antihypertensive treatment (if any). They were followed-up for a 58 (6-234) month period. We confirmed that hypertension is more common among Type 1 diabetic patients than in the general population and found the prevalence of essential hypertension similar in Type 1 diabetic patients to the non-diabetic population. This supports our hypothesis that hypertension is very unlikely to be the cause of diabetic nephropathy.

Islet amyloid polypeptide in diabetic and non-diabetic Pima Indians.

Abstract: Islet amyloid may have a pathological role in the development of Type 2 (non-insulin-dependent) diabetes mellitus. The prevalence of islet amyloid has been investigated on post-mortem pancreatic tissue from both diabetic and non-diabetic Pima Indian subjects who had previously been assessed by oral glucose tolerance tests. Islets were examined for amyloid deposits and for cellular immunoreactivity to pancreatic hormones and islet amyloid polypeptide, the constituent peptide of islet amyloid. Twenty of 26 diabetic subjects (77%) had islet amyloid, compared with one of 14 non-diabetic subjects (7%). Twelve of the diabetic subjects (46%) had amyloid in more than 10% of their islets, whereas only 4% of islets were affected in a single non-diabetic subject. Positive immunoreactivity for islet amyloid peptide was present in the islet amyloid and in islet cells in 54% of the diabetic and 50% of the non-diabetic subjects. Islet amyloid in diabetic Pima Indians may indicate a primary Beta-cell defect which interacts with insulin resistance to produce diabetes, or may develop as a result of Beta-cell dysfunction induced by insulin resistance and hyperglycaemia.

Prognosis after stroke in diabetic patients. A controlled prospective study.

Abstract: Cohorts of diabetic (n=121) and non-diabetic (n=584) patients were prospectively followed for up to ten years after having suffered from a stroke. All but six of the diabetic patients had Type 2 (non-insulin-dependent) diabetes mellitus. The diabetic patients had more risk factors associated with stroke: heart failure (p<0.001) and angina pectoris (p<0.001), than the non-diabetic patients. Neither body mass index nor blood pressure levels differed between the groups at admission. Haematocrit levels were higher in the diabetic group (p<0.01). The diabetic patients were more commonly afflicted by cerebral embolism and to a lesser extent by transient ischaemic attacks than the nondiabetic patients. When calculated by log-rank tests, the diabetic group had an increased risk of death (p<0.001), recurrent stroke (p=0.001), and of myocardial infarction (p=0.001) after the initial stroke. Autopsy-verified causes of death between the groups did not differ significantly, although half of all deaths during the period one to six months after stroke were caused by pulmonary embolism in the diabetic group. Thus, diabetes increases the risk of death after a stroke, and it also increases among stroke survivors the risk of recurrent stroke and myocardial infarction.

Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with type 1 (insulin-dependent) diabetes.

Abstract: Both hypoglycaemia and alcohol consumption affect cognitive function but it is unclear whether moderate drinking alters awareness of hypoglycaemia. We have examined this in a single blind randomised hyperinsulinaemic clamp study in eight non-diabetic subjects and seven Type 1 (insulin-dependent) diabetic patients. After 30 min of euglycaemia (blood glucose 4.5 mmol/l) subjects drank either 0.75 g/kg ethanol or a placebo drink after which blood glucose was lowered to 2.5 mmol/l for 40 min. Awareness of hypoglycaemia, reaction time and physiological responses were measured before and after ethanol. At a blood glucose concentration of 4.5 mmol/l, ethanol (producing peak blood levels of 20–25 mmol/l) caused a transient increase in systolic blood pressure (p<0.05), a sustained increase in heart rate (p<0.01) and a slowing of reaction time in both normal subjects and diabetic patients. During hypoglycaemia in both groups, the slowing of reaction time and increase in sweating were more marked after ethanol than placebo (both p<0.05), while the increase in finger tremor (p<0.05) was blunted after ethanol, in both groups. Counter regulatory hormone secretion was not affected by ethanol. Despite increases in symptoms during hypoglycaemia, only 2 of 15 individuals “felt hypoglycaemic” after ethanol compared to 11 out of 15 after placebo. We conclude that after moderate drinking non-diabetic subjects and Type 1 diabetic patients are less aware of hypoglycaemia despite exaggerated physiological changes.

Enalapril reduces microalbuminuria in young normotensive type 1 (insulin-dependent) diabetic patients irrespective of its hypotensive effect.

Abstract: The effect of enalapril on albumin excretion rate was studied in two groups of age- and sex-matched Type 1 (insulin-dependent) diabetic patients, aged 15–20 years, with persistent microalbuminuria >20 μg/min. Group 1 contained six patients with systolic blood pressure ≥ 75th percentile for age and sex, group 2 six normotensive patients. Enalapril (10–20 mg/day) was given for six months. Albumin excretion rate, glomerular filtration rate, renal plasma flow, blood pressure at rest and during exercise, and angiotensin converting enzyme activity were measured before, after three weeks' and six months' treatment and six months after treatment withdrawal. Albumin excretion rate decreased in all patients after three weeks' (mean decreases 55% in group 1, 65% in group 2) and six months' treatment (35% in group 1, 61% in group 2). Systolic blood pressure remained unchanged in both groups. Diastolic pressure was reduced after three weeks in group 1 (p=0.001). No reduction in increment in systolic pressure during exercise test occurred in any group during treatment. Angiotensin converting enzyme activity decreased in all patients after three weeks (p=0.001) and six months (p=0.003). This correlated to the decrease in albumin excretion rate after three weeks (r=0.79, p=0.05) and six months (r=0.59, p=0.04). HbA1c, mean blood glucose and glomerular filtration rate remained unchanged during the study in both groups. Renal plasma flow tended to increase after three weeks' and six months' treatment in group 2 (p=0.06, respectively) but not in group 1. Filtration fraction decreased after three weeks (p=0.04) only in group 2. In conclusion, enalapril reduces the albumin excretion rate in adolescent diabetic patients with or without elevated blood pressure. This reduction was not accompanied by a decreased systemic pressure but rather by a fall in filtration fraction in normotensive patients, indicating a direct effect, irrespective of the antihypertensive, on intraglomerular pressure.

Myo-inositol and prostaglandins reverse the glucose inhibition of neural tube fusion in cultured mouse embryos.

Abstract: Neural tube defects in infants of diabetic mothers constitute an important and frequent cause of neonatal mortality/morbidity and long-term chronic handicaps. The mechanism by which normal neural tube fusion occurs is not known. The failure of rostral neural tube fusion seen in mouse embryos incubated in the presence of excess-D-glucose can be significantly prevented by the supplementation of myo-inositol to the culture medium. This protective effect of myo-inositol is reversed by indomethacin, an inhibitor of arachidonic acid metabolism leading to prostaglandin synthesis. Prostaglandin E2 added to the culture medium completely protects against the glucose-induced neural tube defect. These data suggest that the failure of neural tube fusion seen in diabetic embryopathy is mediated through a mechanism involving abnormalities in both the myo-inositol and arachidonic acid pathways, resulting in a functional deficiency of prostaglandins at a critical time of neural tube fusion.

Islet cell antibodies and fasting C-peptide predict insulin requirement at diagnosis of diabetes mellitus

Abstract: The differential diagnosis between Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes is complicated since no specific markers are available for either disease. In this study, 244 consecutive patients were diagnosed with diabetes mellitus during two years in Malmo (230000 inhabitants), corresponding to an incidence rate of 53·100000−1·year−1. Age, body mass index, HbA1c, C-peptide, and levels of islet cell antibodies were determined at the clinical onset, and related to the classification at diagnosis and at follow-up (n=233) after a median time of 31 (range 1–49) months. After diagnosis, 42 of 244 (17%) were started on insulin while 202 of 244 (83%) were not. Islet cell antibodies were present in 25 of 42 (60%), and in 18 of 183 (10%), respectively. In the non-insulin treated group, patients with islet cell antibodies had lower body mass index (p<0.001), higher HbA1c (p<0.004), and lower C-peptide (p<0.001) than patients without. At follow-up, 11 of 18 (61%) islet cell positive patients were changed to insulin treatment, as were six other patients. Insulin was discontinued in five initially insulin-treated but islet cell antibody negative patients. The sensitivity, specificity and predictive value for insulin treatment at follow-up were for islet cell antibody positivity; 72%, 96% and 84%, respectively, and for low C-peptide value; 60%, 96%, and 80%, respectively. Islet cell antibodies and low C-peptide at diagnosis of diabetes mellitus are concluded to be useful markers to predict insulin dependence.

Acute and chronic effects of hyperglycaemia on glucose metabolism.

Abstract: In normal man, several hormonal and metabolic adjustments allow the maintenance of the blood glucose concentration within narrow limits Hyperglycaemia participates in this regulation via stimulation of glucose disposal and inhibition of glucose production The effects are mediated, in addition to changes in insulin and glucagon secretion, by the mass-action effect of glucose In both Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients, hyperglycaemia, by mass-action abnormally elevates the basal glucose utilization rate but compensates for reduced postprandial insulin-stimulated glucose disposal When exposed to chronic hyperglycaemia, the body tissues seem to protect themselves, at least partly, against excessive glucose utilization These protective mechanisms include both a reduction in insulin stimulated glucose disposal and insulin secretion Chronic hyperglycaemia may also reduce non-insulin-dependent glucose utilization, at least in rats In Type 1 diabetic patients with normal peripheral insulin concentrations, chronic hyperglycaemia per se could be a major cause of insulin resistance In Type 2 diabetic patients, insulin resistance is often already present before the development of overt fasting hyperglycaemia At the diabetic stage, hyperglycaemia could, however, maintain a self-perpetuating cycle, where the deleterious effects of high glucose concentrations on insulin action and secretion cause further deterioration of glycaemic control The biochemical basis for hyperglycaemia-induced insulin resistance is still far from clear, but could involve changes in the glucose transporter number and gene expression

Islet amyloid polypeptide amide causes peripheral insulin resistance in vivo in dogs.

Abstract: Islet amyloid polypeptide is a 37 amino acid hormone-like peptide which is the major protein component of islet amyloid deposits commonly found in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Recent studies indicate that a physiologically active form of this peptide appears to be carboxyamidated and secreted from the insulin-producing beta cell. In order to clarify the possible in vivo actions of islet amyloid polypeptide, we have studied the effects of synthesized islet amyloid polypeptide-amide on peripheral glucose utilization by performing hyperinsulinaemic euglycaemic glucose clamp studies on dogs. Exogenously administered islet amyloid polypeptide-amide (an infusion from 1.0 to 100 μg·kg−1·h−1, over 2 h) inhibited the insulin-stimulated glucose disposal rate in a dose dependent manner. Twenty-five μg·kg−1·h−1 of islet amyloid polypeptide-amide infused via a peripheral vein significantly lowered the glucose disposal rate by 20% (from 17.4±1.7 to 14.4±1.7 mg·kg−1·min−1, n = 5, p<0.01). These findings suggest that islet amyloid polypeptide-amide causes peripheral insulin resistance in vivo.

Increased blood pressure and erythrocyte sodium/lithium countertransport activity are not inherited in diabetic nephropathy.

Abstract: Genetic predisposition to essential hypertension, represented by maximal erythrocyte sodium/lithium countertransport activity, has been suggested as a marker for the risk of developing clinical nephropathy in Type 1 (insulin-dependent) diabetes mellitus. To evaluate this hypothesis we measured arterial blood pressure and maximal sodium/lithium countertransport activity of erythrocytes in 80 parents of 49 Type 1 diabetic patients with clinical nephropathy, 78 parents of 49 normoalbuminuric patients and 17 age-matched non-diabetic individuals. The two diabetic groups were carefully matched. In the two groups of parents blood pressure and cell sodium/lithium countertransport activity showed no significant differences (137/83 vs 133/81 mmHg and 0.33 vs 0.32 mmol/(1 cells x h) respectively). The proportion of parents who had died or received anti-hypertensive drugs was similar in the two groups.

Reduction of insulin resistance by combined kidney-pancreas transplantation in type 1 (insulin-dependent) diabetic patients.

Abstract: To evaluate the effect of combined kidney and pancreas transplantation on insulin action and glucose metabolism, 15 Type 1 (insulin-dependent) diabetic patients who were undergoing combined kidney-pancreas transplantation were studied before transplantation by means of the euglycaemic hyperinsulinaemic clamp technique combined with 3-3H-glucose infusion and indirect calorimetry. Nine of the original 15 patients were studied again after four months and six after 12 months, successful combined kidney-pancreas transplantation with the same experimental protocol. Nine volunteers formed the group of normal subjects. Combined kidney-pancreas transplantation normalised hepatic glucose production and reduced peripheral insulin resistance in Type 1 diabetic uraemic patients, despite chronic immunosuppressive therapy. To further evaluate the hypothesis that residual insulin resistance was due to chronic steroid therapy, 11 additional subjects with chronic uveitis (six of whom were treated with only prednisone, and five treated only with cyclosporin) underwent the same protocol demonstrating a normal hepatic glucose production. The insulin-stimulated peripheral glucose uptake was reduced in the prednisone-treated group, but normal in cyclosporin-treated subjects. Four additional diabetic patients with a kidney transplant were also studied. They showed a peripheral insulin sensitivity intermediate between diabetic uraemic patients and patients after combined transplant. We conclude that short-term (one year) combined kidney-pancreas transplantation improves glucose metabolism by restoring normal rates of hepatic glucose production and reducing peripheral insulin resistance; chronic steroid therapy is the major determinant of residual reduced insulin action. Both kidney and pancreas substitution play a role in reducing peripheral insulin resistance.

Examination of islets in the pancreas biopsy specimens from newly diagnosed type 1 (insulin-dependent) diabetic patients.

Abstract: We attempted to examine the immunopathological change of the pancreatic islets of newly diagnosed Type 1 (insulin-dependent) diabetic patients and thereby to obtain useful information for the therapy of the patients. For this purpose, pancreas biopsy under laparoscopy was performed 2-4 months after the onset of Type 1 diabetes in seven newly diagnosed patients. All biopsies were performed safely without any complications. Immunohistochemical examination of the biopsy specimens revealed a marked decrease of insulin-containing cells, preservation of glucagon-containing cells, and various degrees of expression of MHC class I and class II antigens in islet cells and in endothelial cells within and around the islets. Signs of active autoimmune phenomena, e.g. lymphocytic infiltration or immunoglobulin deposition in islets, were not detected in any of these patients by light microscopical evaluation. We conclude that pancreas biopsy under laparoscopy has shown various immunological changes in the islets of newly diagnosed Type 1 diabetic patients. Pancreas biopsy, however, may not be suitable under the present protocol for the selection of patients for immunotherapy because of problems including sampling errors.

Kidney IGF-I mRNA in initial renal hypertrophy in experimental diabetes in rats

Abstract: It has recently been demonstrated that immunoassayable kidney insulin-like growth factor I concentration increases 24–48 h after induction of diabetes, preceding the initial renal hypertrophy. To elucidate whether this increase is due to increased local production we studied rat kidney insulin-like growth factor I gene expression during the first four days after induction of streptozotocin diabetes. Eighteen hours after injection with streptozotocin the diabetic animals were divided into two groups, one of which was treated with insulin, and daily for four days animals from each group were taken out for investigation. After four days the wet kidney weight had increased from baseline by 20% (from 687±23 to 827±6mg (mean±SEM), p < 0.01) in the untreated diabetic group, while no significant increase occurred in the insulin-treated group (687±23 vs 732±21 mg, NS). Kidney insulin-like growth factor I increased rapidly from baseline, the rise amounting to 52% after 48 h (from 271±11 to 411±32 ng/g, p < 0.01) with a decline to control level on day four in the untreated diabetic group. Kidney insulin-like growth factor I remained unchanged in the insulin-treated diabetic group. Insulin-like growth factor I mRNA was measured by solution-hybridization assay. No differences were found in kidney insulin-like growth factor I mRNA between the two diabetic groups over the study period, while in liver, insulin-like growth factor I mRNA tended to be lower on day four in diabetic rats when compared to insulin-treated rats (p=0.07). These results show that the increase in kidney insulin-like growth factor I during initial renal hypertrophy in experimental diabetes is not associated with an elevated level of kidney insulin-like growth factor I mRNA and suggest that other, possibly translational, mechanisms are responsible for insulin-like growth factor accumulation in the kidney.