Outpatient treatment of juvenile-onset diabetes with a preprogrammed portable subcutaneous insulin infusion system

Seven patients with juvenile-onset, insulin-dependent diabetes (aged 13 to 32 years) were continuously treated for 12 to 32 weeks while out of the hospital in their usual environment with a portable, batterypowered infusion pump which delivers insulin subcutaneously in basal (between-meal) doses with pulse dose increments before meals. Mean blood glucose levels (237 ± 28 mg/dl during conventional insulin therapy) fell to 105 ± 5 mg/dl after four weeks of pump treatment (p < 0.01) and were maintained at 80 to 104 mg/dl as pump treatment was continued beyond eight weeks. Glycosylated hemoglobin levels (16.0 ± 1.5 per cent before pump therapy) also fell within two weeks (p < 0.01) reaching normal values (9.9 ± 0.3) after eight weeks of pump therapy. Mean plasma cholesterol and triglyceride levels were elevated during conventional therapy and fell to normal after pump treatment. After the first month of pump treatment, only minor adjustments in insulin dose (< 5 per cent of total daily dose) were made. No episode of mechanical pump failure occurred during the 1,110 patient-days of treatment. Overinsulinization and underinsulinization due to human error were relatively rare (four and six episodes, respectively) and failed to result in symptoms of hypo- or hyperglycemia. All patients performed their usual home, work or school activities during pump treatment. We conclude that normalization or near normalization of blood glucose levels can be achieved with a portable subcutaneous insulin infusion system when continuously used to treat patients with juvenile-onset, insulindependent diabetes outside the hospital for three to eight months.     

The Effects of Lipid Lowering Drugs on Metabolic Control and Lipoprotein Composition in Type 2 Diabetic Patients with Mild Hyperlipidaemia

Patients with Type 2 diabetes are at increased risk from macrovascular disease whether or not they are hyperlipidaemic. Several factors may contribute to this increased risk including abnormalities of lipoprotein composition. The aim of our study was to determine the effects of lipid lowering drugs on lipoprotein composition (lipoprotein fractions were separated by sequential flotation ultracentrifugation) and insulin sensitivity (measured by a modified Harano technique) in 44 patients with mild hyperlipidaemia. All patients had total cholesterol concentrations between 5.2 and 6.5 mmol l^?1 and total triglyceride concentrations < 3.0 mmol l^?1, and were randomized by minimization to receive treatment for 12 weeks with bezafibrate, acipimox, simvastatin or placebo. Total cholesterol concentrations were decreased by simvastatin, 5.7 ± 0.4 to 3.7 ± 0.6 mmol l^?1 (p < 0.05), due mainly to reduced LDL-cholesterol levels (?1.25 mmol l^?1; p < 0.05), and bezafibrate 5.7 ± 0.6 to 4.6 ± 0.4 mmol l^?1 (p < 0.05). The LDL:HDL-cholesterol ratio was reduced in the simvastatin group 2.0 ± 0.5 to 1.2 ± 0.3 (p < 0.005). There was no effect of the drugs on glycated haemoglobin or insulin sensitivity. In conclusion bezafibrate and simvastatin improve the lipid profile in Type 2 diabetic patients without adversely affecting diabetic control.     

Amelioration of streptozotocin-induced diabetes in rats: effect of islet isografts on plasma lipids and other metabolic abnormalities.

Administration of streptozotocin in rats results in many metabolic abnormalities, including hyperlipidemia. Plasma triglycerides, cholesterol, insulin, and glucose levels were compared in normal rats, in rats with streptozotocin-induced diabetes, and in streptozotocin-injected rats ameliorated of diabetes 1 mo later by transplantation of adult or neonatal islets to the liver or the lung. Mean plasma glucose levels were 98 ± 4 mg/dl in normal rats, 504 ± 36 mg/dl in untreated diabetic rats, and 139 ± 18, 146 ± 9, and 117 ± 19 mg/dl in recipients of intraportal adult islets, intraportal neonatal islets, and i.v. neonatal islets, respectively; the glucose levels in the recipients of intraportal islets were significantly higher than in normal rats. Mean plasma insulin levels were 23 ± 4 μU/ml in normal rats, 12 ± 5 μU/ml in diabetic rats, and 46 ± 14, 84 ± 25, and 30 ± 5 μU/ml in recipients of intraportal adult islets, intraportal neonatal islets, and i.v. neonatal islets, respectively; the insulin levels in the recipients of intraportal islets were also significantly higher than those in normal rats. Mean plasma triglyceride levels were 35 ± 3 mg/dl in normal rats, 280 ± 72 mg/dl in diabetic rats, and 49 ± 9, 58 ± 8, and 70 ± 4 mg/dl in recipients of intraportal adult islets, intraportal neonatal islets, and i.v. neonatal islets, respectively; the levels in recipients of neonatal islets were significantly higher than those in normal rats. Mean plasma cholesterol levels were 122 ± 10 mg/dl in normal rats, 88 ± 13 mg/dl in diabetic rats, and 105 ± 10, 166 ± 19, and 114 ± 18 mg/dl in recipients of intraportal adult islets, intraportal neonatal islets, and i.v. neonatal islets, respectively; the levels were significantly higher than normal only for the group receiving neonatal islet tissue via the portal vein. Islet transplantation ameliorated diabetes, but mild hyperglycemia persisted even though plasma insulin levels were elevated above normal in recipients of intraportal islets. In addition, plasma triglyceride levels remained slightly elevated after transplantation of neonatal islets, and cholesterol levels were elevated in the group with the highest insulin levels. Possible mechanisms to explain the abnormalities after islet transplantation are discussed. The results indicate the difficulty in restoring completely normal metabolism by ectopic islet transplantation in diabetic recipients.     

Role of candidate genes in the lipid responses to intensified treatment in Type 2 diabetes

OBJECTIVE: To identify genetic factors related to individual differences in lipid responses to intensified treatment in Type 2 diabetes. Design and METHODS: After evaluation and intensification of their treatment, 107 Type 2 diabetes patients with poor metabolic control were re-evaluated after mean follow-up time of 15.6 (0, 4) (SE) months. The genes coding major lipid regulatory proteins and their relations to plasma lipid and lipoprotein changes were studied. RESULTS: During the follow-up, levels of glycohemoglobin A1 (GHBA1) decreased (-1.7%), plasma HDL cholesterol (+0.05 mmol/l) and lipoprotein (a) [Lp(a)] (+4.2 mg/dl) increased, while triglyceride (TG) levels decreased (-1.2mmol/l) despite mean weight gain of 2.1 kg (p from <0.01 to <0.001). Of the gene markers studied, the lipoprotein lipase (LPL) Pvull (p=0.005) independently affected changes in HDL-cholesterol and was associated with the frequency of coronary heart disease (CHD). Lp(a) changes were associated with apolipoprotein B (ApoB) Glu4154Lys polymorphism (p=0.004). CONCLUSIONS: These results suggest that genetic variations at LPL and ApoB loci are among the factors contributing to the variability in response to lipid parameters to therapy in Type 2 diabetes. LPL Pvull rare allele homozygote status seems to be beneficial with more favorable lipid changes and protection against CHD.     

Plasma Lipid Levels at Diagnosis in Type 2 Diabetic Patients

Plasma lipid measurements were obtained at the time that 545 subjects were screened for diabetes mellitus. Both the women and men diagnosed with diabetes had significantly higher triglyceride levels (p < 0.05) and lower high-density-lipoprotein cholesterol (HDL-cholesterol) levels (p < 0.05) than those with normal glucose tolerance. Low-density-lipoprotein cholesterol (LDL-cholesterol) levels were only higher in the diabetic women (p < 0.001). Differences in lipid values were diminished somewhat with allowances for the waist-hip ratio. HDL-cholesterol values were inversely related to fasting insulin levels in the normoglycaemic men and women (p < 0.01), but not in the diabetic individuals. Triglyceride levels were strongly positively related to insulin values in the normoglycaemic men and women (p < 0.001 for both), while associations tended to be smaller in the diabetic subjects. In 13 of the diabetic individuals who were not medicated for diabetes over a period of 17.5 ± 4.6 months, changes in HDL-cholesterol levels were positively related (p = 0.80, < 0.001) and changes in tryglyceride levels inversely related (r = –0.70, p < 0.01) to changes in insulin values. These data indicate that at diagnosis Type 2 diabetic patients have an atherogenic lipid pattern that may be related in part to differences in adipose distribution. In addition, the data suggest that HDL-cholesterol is positively related and triglyceride inversely related to insulin action.     

Plasma apolipoprotein E, high density lipoprotein1 (HDL1) and urinary mevalonate excretion in pancreatectomized diabetic dogs: effects of insulin and lovastatin

Hypercholesterolemia and increased concentrations of an apolipoprotein E (apoE)-containing HDL subclass, high density lipoprotein1 (HDL1) have been observed in streptozocin-alloxan diabetic dogs consuming normal amounts of dietary cholesterol. The aim of this study was to characterize the response of HDL1 and its targeting ligand, apoE, to insulin and HMG-CoA reductase inhibitor treatment in pancreatectomized diabetic dogs. Following induction of diabetes, plasma total cholesterol, HDL1, and apoE concentrations were all increased. Urinary mevalonate excretion, an index of cholesterol synthesis in humans, was 6-fold that of nondiabetic controls. Lipoprotein fractionation by Pevikon block electrophoresis and gel filtration chromatography showed that the increased cholesterol and apoE were associated with alpha 2-migrating particles corresponding to HDL1. Insulin treatment, resulting in near normal fasting blood glucose concentrations in the group as a whole (average 5.1 mM, 92 mg/dl), led to variable reductions in apoE, total plasma cholesterol, and HDL1. Uncorrected dyslipidemia during intensified insulin treatment appeared to be related to failure to achieve euglycemia. Despite unremitting hyperglycemia, treatment with lovastatin resulted in pronounced decreases in plasma cholesterol, HDL1 and apoE to concentrations below those observed in nondiabetic animals. Mevalonate excretion also fell, but remained twice normal. Thus neither modality corrected all of the abnormalities in canine diabetic dyslipidemia. Since apoE-containing HDL1 may mediate cholesterol traffic between the periphery and the liver (reverse cholesterol transport), the present observations suggest that increased cholesterol synthesis is accompanied by parallel abnormalities in cholesterol flux through the reverse transport pathway in the canine model.     

Reduced plasma high density lipoprotein-cholesterol concentrations need not increase when hyperglycemia is controlled with insulin in noninsulin-dependent diabetes mellitus

The ability of intensive insulin treatment to increase plasma high density lipoprotein (HDL)-cholesterol levels was evaluated in 12 patients with noninsulin-dependent diabetes mellitus. Patients were treated for 6 weeks with one daily morning injection of ultralente insulin, in combination with administration of regular insulin before breakfast, lunch, and dinner. The mean (+/- SEM) fasting plasma glucose concentration fell from 289 +/- 21 to 122 +/- 9 mg/dl (P less than 0.001), and the mean hourly postprandial glucose concentration fell from 313 +/- 24 to 102 +/- 7 mg/dl (P less than 0.001). In addition, insulin treatment was associated with a reduction in both fasting plasma triglyceride (256 +/- 45 to 137 +/- 18 mg/dl; P less than 0.001) and cholesterol (224 +/- 25 to 199 +/- 19 mg/dl; P less than 0.05) concentrations. However, plasma HDL-cholesterol concentrations, which were low to begin with, did not rise in association with excellent glycemic control. These results demonstrate that hyperglycemia and hypertriglyceridemia can be effectively reduced by an aggressive program of insulin treatment in patients with noninsulin-dependent diabetes mellitus, but this intervention need not lead to an improvement in the abnormal HDL-cholesterol metabolism in these patients.     

Improved Blood Glucose Control by Insulin Therapy in Type 2 Diabetic Patients Has No Effect on Lipoprotein(a) Levels

The effects of improved blood glucose control by insulin therapy on lipoprotein(a) and other lipoproteins were studied in 54 patients with Type 2 diabetes (mean ± SD: age 67 ± 9 years, body mass index 26.1 ± 4.4 kg m^?2, median duration of diabetes 10 (range 1–37) years, 23 males, 31 females), who were poorly controlled despite diet and maximal doses of oral hypoglycaemic agents. After 6 months of insulin treatment, mean fasting blood glucose concentrations had decreased from 14.1 ± 2.2 mmol l^?1 to 8.4 ± 1.8 mmol l^?1 (p < 0.001), and HbA^1c had fallen from 11.1 ± 1.4 % to 8.2 ± 1.1 % (p < 0.001). Significant decreases of total and LDL cholesterol, triglycerides, apolipoprotein B, and free fatty acids were observed, while HDL-cholesterol and apoA1 increased by 10 %. Baseline serum Lp(a) levels were elevated compared to non-diabetic subjects of similar age (median 283, range 8–3050 mg I^?1, vs 101, range 8–1747 mg I^?1, p < 0.05), but did not change with insulin, and there was no correlation with the degree of metabolic improvement and changes in Lp(a) levels. It is concluded that improved blood glucose control by insulin therapy does not alter elevated Lp(a) levels in Type 2 diabetic patients, but has favourable effects on the other lipoproteins.     

Plasma lipoprotein abnormalities in type 1 (insulin-dependent) diabetes mellitus

Lipoprotein abnormalities may well contribute to the increased risk of coronary heart disease, cerebrovascular disease and peripheral vascular disease observed in type 1 (insulin-dependent) diabetes mellitus. The spectrum of diabetes-associated changes in lipoprotein metabolism is discussed. The plasma levels of lipoprotein cholesterol and triglycerides are largely influenced by the degree of glycaemic control. With poor metabolic control, plasma cholesterol and triglycerides are frequently elevated. In contrast, in well-regulated patients without micro- and macrovascular complications lipid levels are generally normal or even favourable, although lipoprotein composition abnormalities can persist despite intensified insulin treatment. With the development of diabetic nephropathy the cardiovascular risk increases markedly and this complication is associated with increased concentrations of cholesterol and of the atherogenic lipoprotein species, lipoprotein(a), and low levels of high-density lipoprotein cholesterol. The rationale for treatment of lipid disorders in diabetes mellitus is based upon results of trials conducted primarily in non-diabetic populations. It is hoped that with increased recognition of dyslipidaemia and aggressive therapeutic measures the overkill in diabetes mellitus from macrovascular diseases will be reduced.     

The effect of gemfibrozil on lipid profile and glucose metabolism in hypertriglyceridaemic well-controlled non-insulin-dependent diabetic patients

We assessed the efficacy of gemfibrozil therapy on lipid profile and glucose metabolism in a large cohort of (type 2) non-insulin-dependent diabetic patients. We enrolled 217 type 2 diabetic patients with plasma triglyceride concentrations equal to or above 2 mmol/l: 110 were randomized to gemfibrozil (600 mg twice daily) and 107 to placebo treatment in a double blind fashion. Each treatment was followed for 20 weeks. To assess postprandial glucose metabolism and insulin secretion, at time 0 and 20 weeks, a standard meal containing 12.5 g of proteins, 40.1 g of carbohydrate, 10 g of lipids was given. No differences in demographic characteristics were observed between patients randomized either to gemfibrozil or to placebo therapy. No differences were observed in total cholesterol and LDL-cholesterol concentration changes between the baseline observations and week 20 of both treatments. At variance, both treatments significantly increased HDL cholesterol. Gemfibrozil treatment significantly decreased plasma triglyceride concentration from 316±84 to 214±82 mg/dl (P < 0.001), whereas with placebo triglyceride levels increased from 318 + 93 to 380 + 217 mg/dl. No changes were observed in non-esterified fatty acid concentrations or in fasting plasma glucose concentrations, in HbA_1C values, insulin and C-peptide concentrations. Gemfibrozil treatment: 1) significantly reduces circulating triglyceride concentration; 2) does not significantly affect cholesterol concentration; 3) does not worsen glucose metabolism. Received: 13 July 1998 / Accepted in revised form: 24 February 1999     

Lack of effects of hyperglycemia on the disposal of 3-hydroxybutyrate in insulin-dependent diabetic patients

There is evidence that hyperketonemia in insulin-dependent diabetes may be aggravated by a decreased disposal rate for ketone bodies. To test the hypothesis that this decrease may be induced by concomitant hyperglycemia through substrate competition at the acetyl-CoA level, 5 young insulin-dependent diabetic subjects received at 2-h iv infusion of 0.9 mmol 3-hydroxybutyrate.kg-1.h-1 at clamped 1. euglycemia (5 mmol/l) and 2. hyperglycemia (11 mmol/l) on separate occasions. To ensure similar metabolic conditions, a low-dose hyperinsulinemic euglycemic clamp was performed during the 5 h preceding the actual studies. Substrate fluxes in muscle were assessed through the forearm technique. The glucose infusion rate was 4.9 and 2.9 mg.kg-1.min-1, and the forearm arteriovenous difference for glucose was 0.72 during hyperglycemia and 0.39 mmol/l (p less than 0.05), during euglycemia. Hyperglycemia did not affect circulating levels of free insulin, glucagon, non-esterified fatty acids, 3-hydroxybutyrate (hyperglycemia: 665, euglycemia: 770 mumol/l, p greater than 0.05) or acetoacetate, nor forearm uptake of 3-hydroxybutyrate (hyperglycemia, 152, euglycemia: 168 mumol/l, p greater than 0.05). In conclusion, our results do not suggest any inhibitory role for hyperglycemia in the disposal of ketone bodies. In as much as extrapolation from the present well insulinized state is appropriate, the data indicate that alternative mechanisms may be involved in the observed impairment of ketone body clearance in hyperketonemic insulin-dependent diabetic patients.     

The Effect of Intensive Insulin Therapy on the Insulin-regulatable Glucose Transporter (GLUT4) Expression in Skeletal Muscle in Type 1 Diabetes

Studies in normal man and rodents have demonstrated that the expression of the dominant glucose transporter in skeletal muscle, GLUT4, is regulated by insulin at supraphysiological circulating levels. The present study was designed to determine whether intensified insulin replacement therapy for 24 h given to patients with Type 1 diabetes in poor metabolic control was associated with an adaptive regulation of GLUT4 mRNA and protein levels in vastus lateralis muscle. Nine Type 1 diabetic patients with a mean HbA_1c of 10.3% were included in the protocol. After intensified treatment with soluble insulin for 24 h the fasting plasma glucose concentration decreased from 20.8 ± 2.3 (SD) to 8.7 ± 2.3 mmol 1^?1 whereas the fasting serum insulin level increased from 0.06 ± 0.02 to 0.17 ± 0.09 nmol 1^?1 However, despite a 2.8-fold increase in serum insulin levels and more than a halving of the plasma glucose concentration for at least 15 h no significant alterations occurred in the amount of GLUT4 protein (0.138 ± 0.056, poor control vs 0.113 ± 0.026 arb. units, improved control, p = 0.16) or GLUT4 mRNA (96432 ± 44985, poor control vs 81395 ± 25461 arb. units, improved control, p = 0.54). These results suggest, that in spite of evidence that high insulin levels affect GLUT4 expression in muscle, changes in serum insulin within the physiological range do not play a major role in the short-term regulation of GLUT4 expression in Type 1 diabetic patients.     

Minimal response of circulating lipids in women with polycystic ovary syndrome to improvement in insulin sensitivity with troglitazone

We hypothesized that the administration of troglitazone (TGZ), an insulin-sensitizing agent of the thiazolidinedione class, would improve dyslipidemia associated with insulin resistance in polycystic ovary syndrome (PCOS). Three hundred and ninety-eight women with PCOS in a multicenter, double-blind trial were randomly assigned to 44 wk of treatment with: placebo or troglitazone (150, 300, or 600 mg/d). We examined the responses of circulating lipid and lipoproteins [total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), and triglycerides (TTG)] by treatment arm, and the influence of glycemic parameters on baseline levels and response to treatment. There was a high prevalence of abnormal baseline lipid parameters, as defined by National Cholesterol Education Program guidelines [total cholesterol, > or = 200 mg/dl (35%); LDL-C, > or = 130 mg/dl (31%); HDL-C, <35 mg/dl (15%); TTG, >200 mg/dl (16%)]. Baseline models showed that parameters of insulin action had poor predictive power on lipid parameters. There was no significant response of any of the circulating lipids to treatment with either placebo or one of the troglitazone arms (after correction for multiple analyses). There were favorable, but nonsignificant, trends in HDL-C (increase) and LDL-C (decrease) and a trend toward decreased circulating TTG in the 300- and 600-mg TGZ dose treatment arms, both in an intention to treat analysis (n = 375) and in study completers (44 wk; n = 152). There also was a minimal treatment effect noted when only subjects with abnormal baseline levels were examined, and responders differed little from nonresponders in terms of indices of insulin action. There is a substantial prevalence of clinically recognized dyslipidemia in the population of women with unrecognized PCOS without type 2 diabetes. Treatment with an insulin-sensitizing agent may have minimal impact on circulating lipids. Further surveillance and treatment of abnormal lipid levels may be necessary in these women.     

The metabolic response to glycemic control by the artificial pancreas in diabetic man.

To determine the effect of glycemic control by the artificial pancreas on the other metabolic consequences of diabetes, five renebese male insulin-dependent diabetic subjects were studied first on s.c. insulin and then during artificial pancreas (AEP) control. Glycemia was continuously monitored, and the circulating concentrations of factate, pyruvate, alanine, free fatty acids (FFA), beta hydroxybutyrate, and triglycerides were measured during breakfast, lunch, snack, and supper. The metabolic profiles were compared to normal control subjects. Glycemic excursion with meals during AEP control was normalized (min, 76 ± 8 mg/dl; max, 157 ± 20 mg/dl), compared to administration of s.c. insulin (min, 173 ± 52; max, 279 ± 49 mg/dl). Postabsorptive concentrations of lactate and pyruvate were elevated for diabetic subjects on s.c. insulin treatment and during AEP control. However, the postmeal peaks of lactate and pyruvate observed in the normal control individuals were restored during AEP control. Although alanine concentrations were similar for all groups at the start of the experiment, the postprandial increase that occurred with breakfast for the normal subjects was delayed until lunch for both diabetic groups. The elevated FFA concentrations with s.c. insulin were entirely normalized during AEP control, whereas beta hydroxybutyrate concentrations were incompletely corrected. These studies demonstrate that a short period of glycemic control during meals restores toward normal other metabolic intermediates influeneed by insulin. For further refinement in metabolic control, a more prolonged period of normoglycemia may be required.     

Hyperlipidemia and atherosclerosis in experimental insulinopenic diabetic monkeys.

Chronic insulinopenic diabetes was induced by i.v. streptozotocin in the non-human primate Macaca fuscata. Five diabetic monkeys were kept for 8-19 months and nine for 24-48 months without any insulin treatment. Hyperglycemia (241 +/- 22 mg/dl, M +/- SE less than or equal to 1 year) progressed to 376 +/- 34 mg/dl (greater than 2 years) and ketosis to 3.5 mM (greater than 2 years) during the course of diabetes; this was roughly inversely proportional to hypoinsulinemia (3.4 microU/ml, 2 years). Serum cholesterol increased from 184 +/- 11 (less than or equal to 1 year) to 328 +/- 66 mg/dl (greater than 2 years) with the major increase in LDL-cholesterol (2.7-fold over control, greater than 2 years). HDL-cholesterol did not change at all throughout the experimental period. TG increased from 144 +/- 25 (less than or equal to 1 year) to 676 +/- 116 (greater than 2 years) with a major increase in the VLDL fraction (15-fold over control, greater than 2 years). Serum levels of apo B increased to 141 +/- 16 (less than or equal to 2 years) and 223 +/- 8 mg/dl (greater than 2 years) in contrast to control, 73 +/- 2. Morphologically, lipid deposition in the intima and fatty streaks have been observed in the abdominal aorta of all the diabetic monkeys with duration of more than 2 years. In six of the diabetic monkeys atheromatous changes such as intimal and medial thickening with smooth muscle cell proliferation were observed with foam cell formation. Similar atherosclerotic lesions were observed in renal and coronary arteries in at least six of these monkeys. In diabetic monkeys with duration of less than 2 years, mild atherosclerotic lesions were observed in two out of five. The results indicate that long standing insulinopenia leads to metabolic derangements characterized by hyperglycemia, ketonemia and hyperlipidemia. Elevation of LDL-cholesterol and VLDL TG with an increase of apo B is a characteristic of lipoprotein disorder. Morphologically, early to moderately advanced lesions of atherosclerosis were observed in aorta, renal and coronary arteries as a result of metabolic derangement due to insulin deficiency.     

Lipid and lipoprotein distributions in octo- and nonagenarians.

This study focused on 124 octogenarians and 13 nonagenarians to extend data on lipid and lipoprotein distributions into the eighth and ninth decades of life and to assess relationships between lipids, lipoproteins, and longevity. The mean (±SD) ages of the 114 women and 23 men were 85 ± 4 and 84 ± 4 yr, respectively. Mean (±SD) total plasma cholesterol and high density lipoprotein cholesterol (C-HDL) were higher in women than in men, 219 ± 41 and 198 ± 31 mg/dl, 58 ± 16 and 50 ± 13 mg/dl respectively, p<.02. Mean (±SD) low density lipoprotein cholesterol (C-LDL) levels were 132 ± 35 in women, 125 ± 26 mg/dl in men. In women, the 90th percentile levels for total plasma cholesterol, C-HDL, C-LDL, and triglyceride were respectively 269, 79, 180, and 243 mg/dl, with the 10th percentile levels being 164, 36, 85, and 77 mg/dl. For both women and men, total plasma cholesterol was closely correlated with C-LDL, r=.937, .926, p<.01. In the eighth and ninth decades of life, reductions in total plasma cholesterol are probably accounted for by reductions in C-LDL levels, while C-HDL remains stable. Subjects living into the eighth and ninth decades may have lower plasma cholesterol and C-LDL and stable C-HDL, because those with higher C-LDL and/or lower C-HDL have been removed from the distribution by coronary heart disease. Alternatively, some octo- and nonagenarians may also come from kindreds having familial hypobeta- or familial hyperalpha-lipoproteinemia, familial traits associated with increased longevity and reduced CHD morbidity and mortality.     

Improved Glycemic Control and Lipid Profile in a Randomized Study of Pioglitazone Compared with Acarbose in Patients with Type 2 Diabetes Mellitus

Objective: To assess the efficacy of pioglitazone treatment in comparison with that of acarbose treatment in patients with type 2 diabetes mellitus. Participants and methods: In this randomized, parallel-group, open-label study patients were assigned to treatment with either pioglitazone (n = 129) or acarbose (n = 136). During a 1-week run-in patients commenced an individualized dietary regimen which was maintained throughout the study. Patients received the assigned study medication for 26 weeks. Serum glycosylated hemoglobin (HbA_1c) levels, insulin resistance and lipid profiles were determined at baseline and at endpoint. Results: Mean HbA_1c was reduced from 8.98 ± 1.20% to 7.82 ± 1.95% with pioglitazone treatment and from 9.03 ± 1.32% to 8.55 ± 1.96% with acarbose treatment during the 26-week study. The change from baseline to endpoint was significantly greater for pioglitazone compared with acarbose when analyzed for all patients (p < 0.001) and for those who had (p = 0.009) or had not (p < 0.001) received previous medication for diabetes mellitus. Compared with acarbose, pioglitazone produced a significantly greater decrease in fasting glucose, insulin and insulin resistance (p < 0.001 for each). Triglycerides were decreased by 71.1 ± 184.1 mg/dl with pioglitazone compared with 38.1 ± 171.3 mg/dl with acarbose (p = 0.001 for difference between groups). High density lipoprotein (HDL)-cholesterol level was increased by 7.8 ± 10.2 mg/dl with pioglitazone compared with a decrease of 0.8 ± 24.1 mg/dl with acarbose (p < 0.001). While serum low density lipoprotein (LDL)-cholesterol levels remained unchanged with both treatment regimens, the decrease from baseline in very low density lipoprotein (VLDL)-cholesterol was significantly greater with pioglitazone than with acarbose (p < 0.04). Pioglitazone decreased systolic blood pressure by 5.6 ± 17.7mm Hg compared with a 0.4 ± 18.4mm Hg increase during acarbose treatment (p < 0.001). Pioglitazone caused a significantly greater decrease compared with acarbose in serum levels of γ-glutamyl aminotransferase (p < 0.001) and alanine aminotransferase (p = 0.004). Conclusions: Six months of pioglitazone treatment decreased insulin resistance and improved glycemic control to a significantly greater extent than acarbose treatment. Pioglitazone was also associated with a significantly improved lipid profile, suggesting a reduction in risk of coronary heart disease.     

Hormone-fuel metabolism during exercise of insulin-dependent diabetic patients treated with an artificial B-cell unit

Summary The effects of restoration of glucose homeostasis on hormone-fuel metabolism of diabetic individuals during exercise (40% maximal O₂ consumption) were determined by monitoring fuel oxidation rates and levels of substrates and hormones in nine normal subjects and five insulin-dependent diabetic patients while on conventional insulin therapy and after 3 days on artificial B-cell directed glucose regulation. The non-protein respiratory quotient (npRQ) and carbohydrate oxidation rate of the conventionally-treated diabetic subjects (0.908±0.002 and 538±5 mg/m²·min) were lower and the lipid oxidation rate (101±2 mg/m²·min) was significantly higher than those of the normal group during the bicycle exercise (0.937±0.004, 582±8, and 70±4 mg/m²·min, respectively). After 3 days of artificial B-cell insulin therapy, the npRQ and carbohydrate oxidation rate of the exercising diabetics significantly increased to 0.965±0.004 and 693±13 mg/m²·min, while the lipid oxidation rate declined to 39±4 mg/m²·min (p<0.001). We conclude that artificial B-cell directed insulin therapy increases carbohydrate oxidation and decreases lipid oxidation in exercising insulin-dependent diabetic subjects. However, if restoration of metabolic response identical to that of exercising normals is desired, the excess in carbohydrate oxidation coincident with elevated blood lactate and pyruvate levels suggest that the artificial B-cell therapy may not have been completely optimal, probably due to the hyperinsulinization of the diabetic patients. Research supported by NIH grants AM 15191 and AM 20530, Howard Hughes Medical Institute (U.S.A.), and FAPESP (Brazil) (n ^o 78/1131)     

Mechanism of hypertriglyceridaemia in diabetic patients with fasting hyperglycaemia

Summary Several aspects of lipid metabolism were studied to define the mechanism of hypertriglyceridaemia in insulin-independent diabetic patients with fasting hyperglycaemia. Patients with insulin-independent diabetes were more obese (p<0.001) and had a significantly (p<0.001) higher mean (± SEM) fasting plasma triglyceride concentration (387 ±66 mg/dl) than did either insulin-dependent diabetics (133±11 mg/dl) or normal (73±1 mg/dl) subjects. Very low density lipoprotein secretion rate was also significantly (p<0.01 — <0.001) higher in patients with insulin-independent diabetes (14.65±1.37 mg/kg/h) as compared to 7.64±0.60 mg · kg/h and 9.86±0.75 mg/kg/h in normal subjects and patients with insulin-dependent diabetes, respectively. However, the relationship between plasma triglyceride concentration and very low density lipoprotein-triglyceride secretion was similar in diabetics and in normals. The diabetic groups had equivalent degrees of fasting and postprandial hyperglycaemia, and comparable elevations of fasting plasma nonesterified free fatty acid levels (insulin-independent = 0.72±0.07 mmol/L, insulin-dependent = 0.63±0.08 mmol/L). Postprandial plasma insulin concentrations, however, reached normal levels in insulin-independent diabetics and were higher (p<0.001) than in insulin-dependent diabetics. Thus, hypertriglyceridaemia in insulin-independent diabetics with fasting hyperglycaemia was associated with increased hepatic very low density lipoprotein-triglyceride secretion, and normal plasma insulin levels. The lower triglyceride levels in the insulin-dependent diabetics is assumed to be due to their relative hypoinsulinaemia.     

A circadian rhythm-related MTNR1B genetic variant (rs10830963) modulate body weight change and insulin resistance after 9 months of a high protein/low carbohydrate vs a standard hypocaloric diet

Background & aimsThe risk allele (G) of rs10830963 in the melatonin receptor 1 B (MTNR1B) gene presents an association with biochemical parameters and obesity. We study the effect of this SNP on insulin resistance and weight loss secondary to two hypocaloric diets.Methods270 obese subjects were randomly allocated during 9 months (Diet HP: a high protein/low carbohydrate vs. Diet S: a standard severe hypocaloric diets). Anthropometric parameters, fasting blood glucose, C-reactive protein (CRP), insulin concentration, insulin resistance (HOMA-IR), lipid profile and adipocytokines levels were measured. Genotype of MTNR1B gene polymorphism (rs10830963) was evaluated.ResultsAll adiposity parameters, systolic blood pressure and leptin levels decreased in all subjects after both diets. This improvement of adiposity parameters was higher in non-G allele carriers than G allele carriers. After weight loss with Diet HP, (CC vs. CG + GG at 9 months); total cholesterol (delta: −9.9 ± 2.4 mg/dl vs. −4.8 ± 2.2 mg/dl:p < 0.05), LDL-cholesterol (delta: −8.3 ± 1.9 mg/dl vs. −5.1 ± 2.2 mg/dl: p < 0.05), insulin (delta: −4.7 ± 0.8 UI/L vs. −0.9 ± 1.0 UI/L: p < 0.05), triglycerides (delta: −17.7 ± 3.9 mg/dl vs. −6.1 ± 2.8 mg/dl: p < 0.05) and HOMA IR (delta: −0.8 ± 0.2 units vs. −0.2 ± 0.1 units: p < 0.05) improved only in no G allele carriers. After weight loss with Diet S in non G allele carriers, insulin levels (delta (CC vs. CG + GG): −3.4 ± 0.6 UI/L vs. −1.2 ± 0.4 UI/L: p < 0.05), triglycerides (delta: −29.2 ± 3.4 mg/dl vs. −8.2 ± 3.8 mg/dl: p < 0.05), HOMA-IR (delta (CC vs. CG + GG): −1.1 ± 0.2 units vs. −0.1 ± 0.1 units: p < 0.05), total cholesterol (delta: −15.9 ± 7.4 mg/dl vs. −5.8 ± 2.9 mg/dl:ns) and LDL-cholesterol (delta: −13.7 ± 5.9 mg/dl vs. −6.0 ± 2.9 mg/dl: ns) decreased, too.Conclusionsour study detected a relationship of rs10830963 variant of MTNR1B gene with adiposity changes, cholesterol changes and insulin resistance modification induced by two different hypocaloric during 9 months.