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In muscle, hexokinase II (HK2) regulates phosphorylation of glucose to glucose 6-phosphate, which has been reported to be impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM). Here we report decreased HK2 enzyme activity in skeletal muscle biopsies from patients with impaired glucose tolerance compared with healthy control subjects (2.7 +/- 0.9 vs 4.9 +/- 1.1 nmol.min-1.mg protein-1). Therefore, mutations in the HK2 gene could contribute to skeletal muscle insulin resistance in NIDDM. To address this question, we first determined the exon-intron structure of the human HK2 gene and using this information, we screened all 18 exons with single-strand conformation polymorphism technique in 80 Finnish NIDDM patients. Nine nucleotide substitutions were found, one of which was a missense mutation (Gln142-His142) in exon 4. In human muscle, a single HK2 mRNA transcript with a size of approximately 5500 nucleotides was detected with Northern blot analysis. We also describe an HK2 pseudogene (HK2P1), which was mapped to chromosome 4, band q26, by fluorescence in situ hybridization to metaphase chromosomes. The clinical characteristics and HK2 enzyme activities of the subjects with either Gln or His at residue 142 did not differ from each other. Instead, HK2 activity correlated inversely with fasting blood glucose levels, suggesting that changes in HK2 activity could be secondary to other metabolic abnormalities (r = 0.55; p0.0003; n = 39). In conclusion; the data suggest that impaired HK2 activity in prediabetic individuals is a consequence of impaired glucose tolerance rather than of a genetic abnormality. The data thus seem to rule out mutations in the HK2 gene as a major cause of inherited insulin resistance in NIDDM.

Skeletal muscle is a major metabolic organ and plays important roles in glucose metabolism, insulin sensitivity and insulin action. Muscle telomere length reflects the myocyte's exposure to harmful environmental factors. Leukocyte telomere length is considered a marker of muscle telomere length and is used in epidemiologic studies to assess associations with ageing-related diseases where muscle physiology is important. However, the extent to which leucocyte and muscle telomere length are correlated is unknown, as are their relative correlations with glucose and insulin concentrations. The purpose of this study was to determine the extent of these relationships.Leucocyte and muscle telomere length were measured by quantitative real-time polymerase chain reaction in participants from the Malmö Exercise Intervention (n = 27) and the Prevalence, Prediction and Prevention of Diabetes-Botnia studies (n = 31). Participants in both studies were free from Type 2 diabetes. We assessed the association between leucocyte telomere length, muscle telomere length and metabolic traits using Spearmen correlations and multivariate linear regression. Bland-Altman analysis was used to assess agreement between leucocyte and muscle telomere length.In age-, study-, diabetes family history- and sex-adjusted models, leucocyte and muscle telomere length were positively correlated (r = 0.39, 95% CI 0.15-0.59). Leucocyte telomere length was inversely associated with 2-h glucose concentrations (r = -0.58, 95% CI -1.0 to -0.16), but there was no correlation between muscle telomere length and 2-h glucose concentrations (r = 0.05, 95% CI -0.35 to 0.46) or between leucocyte or muscle telomere length with other metabolic traits.In summary, the current study supports the use of leucocyte telomere length as a proxy for muscle telomere length in epidemiological studies of Type 2 diabetes aetiology.

Gastrocnemius muscle morphology, metabolic potential, and capillarization were analyzed in 48-year-old men with regard to subsequent development of non-insulin-dependent diabetes mellitus (NIDDM) in 29 subjects with impaired glucose tolerance (IGT) and in 38 control subjects. Over a 15-year period, although participating in an intervention program, 13 of the IGT subjects developed diabetes, but none of the control subjects developed diabetes. In view of their poor aerobic capacity, lack of physical fitness, and reduced glycolytic and oxidative enzymes, these 13 subjects manifested an unexpectedly high number of capillaries around all types of muscle fibers, especially type IIb fibers, as predictors of their progression to diabetes. Moreover, the number of capillaries per muscle fiber and the 2-h insulin value in the oral glucose tolerance test were highly correlated (r = 0.82, P < 0.005), whereas no correlation was found among IGT subjects who remained nondiabetic and in the control group. With body mass index and the 2-h glucose concentration included in a regression model, 68% of the variation in the number of capillaries per muscle fiber was explained (P < 0.05), with the 2-h insulin value independently accounting for 33%. These findings may suggest that the increased circulating insulin concentrations in IGT subjects have a capillary proliferative effect, perhaps to compensate for reduced capillary insulin diffusion and metabolic capacity of the muscle.

Hyperhomocysteinemia is an independent risk factor for vascular disease. In order to evaluate relations between hyperhomocysteinemia and endothelial and leukocyte function, the investigators related homocysteine to indices of endothelial function (plasma endothelin-1 [p-ET-1] and intraplatelet levels of the nitric oxide [NO] and prostacyclin mediators 3'-5' guanosine monophosphate [cGMP] and cyclic 3'-5' adenosine monophosphate [cAMP]) and the monocyte-derived inflammatory mediator neopterin in 168 men (mean age 69, range 49-72 years) with disturbed glucose metabolism and a reference group of 52 male subjects (mean age 70, range 61-79 years). Among the 168 patients with disturbed glucose metabolism plasma (p)-homocysteine correlated signifi cantly with age (r=0.20; p < 0.01), glycosylated hemoglobin (HbA1c) (r=0.17; p < 0.05), triglycerides (r=0.20; p

Impaired glucose tolerance (IGT) is associated with increased mortality due to ischaemic heart disease (IHD), but as it is not known whether this excess mortality can be reduced by preventing or delaying the development of non-insulin-dependent diabetes mellitus (NIDDM), a long-term NIDDM prevention trial of dietary counselling and physical exercise was launched at Malmo, Sweden, the 12-year follow-up of which is reported here. At 12-year follow-up of 6956 men who underwent health screening at 48 years of age, an IGT intervention group (n = 288) who participated in a long-term NIDDM prevention programme were compared with an IGT non-randomised routine treatment group (n = 135), a diabetic group (n = 144), and the remainder, the normal glucose tolerance (NGT) group (n = 6389). The variables studied included the levels of blood glucose, plasma insulin, blood pressure, blood lipids, lung function and maximum oxygen uptake. Subjects with IGT were characterised by overweight, poor vital capacity, hypertension, hypertriglyceridaemia and hyperinsulinaemia. The mortality rate in the IGT intervention group was similar to that in the NGT group (6.5 vs 6.2 per 1000 person years at risk) and lower than that in the IGT routine treatment group (6.5 vs 14.0, p = 0.009). In the two IGT groups taken together, intervention but not body mass index, systolic blood pressure, smoking, cholesterol or the 2-h glucose level predicted mortality. Systolic blood pressure was a predictor of IHD mortality among IGT subjects; and in the cohort as a whole, body mass index, systolic blood pressure, hypercholesterolaemica, diabetes and smoking were predictors of IHD mortality. The findings suggest that a long-term intervention programme, with an emphasis on lifestyle changes, including dietary counselling and physical exercise, will reduce mortality in subjects with IGT who are at an increased risk of both developing NIDDM and of premature death due to IHD and other causes. [Diabetologia (1998) 41: 1010–1016]

The postoperative effects of a whole sural nerve biopsy in diabetic (11) and non-diabetic (10 healthy controls, 10 patients with impaired glucose tolerance and 2 patients with polyneuropathy) subjects were investigated by a mailed questionnaire 20-44 months after the surgical procedure (10/11 vs 21/22 answers received). Pain in the biopsy area at follow-up was reported in 4/10 of the diabetic patients (p = 0.01) but in none of the non-diabetic subjects (0/21). An increased number (p = 0.01) of diabetic patients (5/10 vs 1/21) had cold intolerance in their foot or leg whereas 11/31 of all patients had dysaesthesia in the affected skin. Overall 6/31 patients described serious problems at the time of the questionnaire, and 4 of this 6 having diabetes. Loss of sensation was reported in almost all subjects irrespective of diabetes or not; however, a decrease in the area of loss of sensation was reported most often in diabetic patients (8/10 vs 8/21, p = 0.02). It is concluded that whole surval nerve biopsies give rise to persistent problems both in diabetic and non-diabetic subjects. The reason for a sural nerve biopsy has always to be carefully considered before being conducted.

In a population study of 6956 middle-aged men, 5% received drug treatment for hypertension, another 25% had a blood pressure of greater than 160.90 mmHg, and 3.2% were diabetic. Prevalence of impaired glucose tolerance and diabetes was two- to threefold in hypertensive subjects, and 50% of the glucose intolerant or diabetic cases had hypertension. In 4677 unselected subjects without clinical coronary heart disease or previous diabetes, estimated insulin resistance (i.e. the 2-h insulin-to-glucose ratio during an oral glucose tolerance test, controlled for body mass index) correlated with both systolic and diastolic blood pressure. In untreated subjects, a diastolic blood pressure of greater than 90 mmHg was found in conjunction with a higher insulin resistance value than predicted, whereafter blood pressure progressively increased. The contribution of drug treatment to insulin resistance was significant, but less than 1% in the whole material and about 2.5% in cases with impaired glucose tolerance.

Seventeen patients were operated on with intestinal shunts for morbid obesity, in eight a biliointestinal bypass (BI) was constructed and in the rest a conventional jejunoileal (JI)-shunt. The reduction in weight was similar in both groups, and so was malabsorption of fat, but the BI-group had significantly less bowel motions with less watery diarrhoea. Bile acid malabsorption was measured both chemically by estimating the total amount of faecal bile acids excreted, as well as indirectly by using a 75Se-labelled synthetic bile acid (SeHCAT). Both techniques revealed a substantial loss of bile acid after both types of operation, but patients with BI bypass surgery had significantly lower elimination time of the bile acid than those with JI-shunts. There was a significant negative correlation between SeHCAT retention and total faecal bile acids. However, some patients with low SeHCAT retention had normal or even reduced output of faecal bile acids. Estimation of faecal bile acids may display false negative results when the bile acid pool is decreased. The SeHCAT-test seems to be a better technique for measuring bile acid losses. The study suggests that BI bypass surgery for obesity seems to be advantageous over the JI shunt in reducing the postoperative loss of bile acids and choleretic diarrhoea, without influencing the weight loss.

3'-Azido-2',3'-dideoxy-5-methylcytidine (CS-92, AzddMeC) is an antiviral nucleoside analogue structurally related to 3'-azido-3'-deoxythymidine (AZT). CS-92 is a potent and selective inhibitor of HIV-1 reverse transcriptase and HIV-1 replication in human lymphocytes and macrophages. The EC50 for CS-92 in HIV-1-infected human PBM cells was 0.09 microM. In HIV-1-infected human macrophages, the EC50 was 0.006 microM. This compound was also effective against human immunodeficiency virus type 2 in lymphocytes. The replication of Friend murine virus was only weakly inhibited, and no effect was observed against herpes simplex virus type 1 and type 2 and coxsackievirus B4. CS-92 was not toxic to PBM or Vero cells when tested up to 200 microM and was, furthermore, at least 40 times less toxic to granulocyte-macrophage and erythroid precursor cells in vitro than was AZT. The interaction of the 5'-triphosphate of CS-92 with HIV-1 reverse transcriptase indicated competitive inhibition (the inhibition constant, Kis, was 0.0093 microM) with a 30-fold greater affinity for CS-92-TP than for ddCTP. CS-92-TP inhibited HIV-1 reverse transcriptase by 50% at a concentration 6,000-fold lower than that which was required for a similar inhibition of DNA polymerase alpha. Pharmacokinetic studies showed that CS-92 was not deaminated to AZT in rats, but this compound was found to have a half-life of 2.7 hours. In rhesus monkeys, however, a compound with a retention time and ultraviolet spectra characteristics similar to AZT was detected. The mean half-life in rhesus monkeys for CS-92 was 1.52 and 1.74 h after intravenous and oral administration, respectively, and the oral bioavailability was about 21 percent. Additional preclinical studies with CS-92 will determine the ultimate utility of this antiviral agent for the treatment of HIV-1 infections.

The transglutaminase involvement in phytohaemagglutinin (PHA) stimulated lymphocyte transformation (measured as (3H)thymidine incorporation) was studied in lymphocytes from 20 patients with type 2 diabetes mellitus and 20 healthy controls by including in the system the specific transglutaminase pseudosubstrate monodansylthiacadaverine (MDTC). In the presence of MDTC, (3H)thymidine incorporation was significantly and concentration-dependently reduced in both groups but more pronouncedly in the diabetes patients. The MDTC concentration needed to give a 50% reduction of the PHA-stimulated (3H)thymidine incorporation was significantly lower in lymphocytes from diabetic patients than in those from controls (p less than 0.02). The data suggest impaired lymphocyte transglutaminase function in type 2 diabetes mellitus.

To eliminate the blind loop in conventional jejunoileal bypass (JIB) and to maintain enteroheptic circulation of bile, thus hoping to diminish important side-effects of JIB, biliontestinal bypass was introduced in 1975, entailing anastomosis of the blind jejunal loop to a functioning gallbladder. Twenty-two patients with a mean weight of 126 kg (91-154 kg) have had primary bilio-intestinal bypass and another four secondary anastomosis of the gallbladder due to side-effects of the previous JIB. A mean weight reduction of 50 kg was achieved in the 20 patients observed for 24 months, without any serious side-effects, corresponding to a reduction of overweight from 89 per cent preoperative to 14 per cent in a subsample of seven patients followed for five years. Without affecting body weight in the four patients subjected to secondary operation, it ameliorated the side-effects of JIB during observation of more than 6 months. Follow-up with i.v. cholangiography and Tc99 HIDA scintigram conclusively revealed open anastomoses in nine of ten patients adequately judged by the scan and no evidence of gallstones on 15 cholangiograms performed so far. Renal calculi were found in three patients, mainly in the first postoperative year but urine oxalate was in the normal range after more than years of follow-up. It is concluded that jejunoileal bypass combined with cholecystojejunostomy in patients with functioning gallbladders is a safe and relatively simple method for treating morbid obesity in selected cases.

Fourteen middle-aged med with impaired glucose tolerance were studied prior to and 6 months after exchange of simple carbohydrates for complex carbohydrates rich in fibers and saturated for polyunsaturated fats in their diet when exchangeable. Body weight was reduced by 6.4 kg (p less than 0.001). Physical work capacity was unchanged. Fasting blood glucose and insulin were lowered (p less than 0.001) at 6 months and so were the values during an OGTT at 120 min. Both serum triglyceride and cholesterol concentrations were reduced (p less than 0.01) by the changes diet, the most marked reduction being found in the VLDL fraction. HDL levels increased by 21% (p less than 0.01). Enzyme activities in gastrocnemius muscle specimens were subnormal and uninfluenced by changed dietary habits. The number of capillaries per fiber was normal throughout, but as muscle fiber size was reduced in relation to the decreased body weight, the number of capillaries/mm2 increased during the dieting period. It is suggested that the observed improvement in insulin sensitivity and glucose tolerance after a dietary period with weight reduction is related to and partly explained by shorter diffusing distances in weight-bearing muscles.

Insulin secretion, work capacity and plasma lipids were evaluated in 52 middle-aged men with impaired glucose tolerance (IGT), and the values were compared with those of 23 normoglycemic subjects with family histories of Type 2 diabetes and of 22 non-hereditary normoglycemic controls. All subjects were non-obese males of comparable age. Estimated maximal oxygen uptake was significantly lower (p less than 0.01) and triglyceride concentrations significantly higher (p less than 0.01) in IGT individuals than in subjects of the non-hereditary normoglycemic group, while no significant differences were noted in comparison with the hereditary group. IGT individuals showed an impaired insulin response to glucose with significantly lower absolute values of insulin and C-peptide during the early phase of the oral glucose tolerance test (OGTT) than in non-hereditary normoglycemic subjects, but not significantly lower than in the hereditary group. Similarly, at most time points of the OGTT the ratios of insulin and C-peptide to glucose were significantly lower in the IGT group than in the non-hereditary group, while these differences were less pronounced in comparison with the hereditary group. These findings suggest some similarities of metabolic disturbances in lean normoglycemics with positive family histories of Type 2 diabetes and in lean IGT individuals. Family history of diabetes (both first degree and second degree only) was significantly more prevalent among IGT individuals than among normals.