acipimox and Diabetes-Mellitus--Type-1

Because GH stimulates lipolysis, an increase in circulating free fatty acid levels, as opposed to a direct effect of high GH levels, could underlie the development of insulin resistance in type 1 diabetes (T1D). Our aim was to explore the relative contributions of GH and free fatty acids to the development of insulin resistance in patients with T1D.. Seven (four females, three males) nonobese patients with T1D aged 21-30 yr were studied on four occasions in random order. On each visit, overnight endogenous GH production was suppressed by octreotide. Three 1-h pulses of recombinant human GH (rhGH) or placebo were administered on two visits each. Acipimox, an antilipolytic drug, or a placebo were ingested every 4 h on two visits each. Stable glucose and glycerol isotopes were used to assess glucose and glycerol turnover. The overnight protocol was concluded by a two-step hyperinsulinemic euglycemic clamp on each visit.. rhGH administration led to increases in the insulin infusion rate required to maintain euglycemia overnight (P = 0.008), elevated basal endogenous glucose production (P = 0.007), decreased basal peripheral glucose uptake (P = 0.03), and reduced glucose uptake during step 1 of the clamp (P < 0.0001). Coadministration of rhGH and acipimox reversed these effects and suppression of lipolysis in the absence of GH replacement led to further increases in insulin sensitivity.. GH pulses were associated with an increase in endogenous glucose production and decreased rates of peripheral glucose uptake, which was entirely reversed by acipimox. Therefore, GH-driven decreases in insulin sensitivity are mainly determined by the effect of GH on lipolysis.

Topics: Adult; Blood Glucose; Diabetes Mellitus, Type 1; Fatty Acids, Nonesterified; Female; Human Growth Hormone; Humans; Insulin Resistance; Male; Pyrazines

During the noninvasive assessment of myocardial viability with (18)F-FDG metabolic imaging, adequate regulation of metabolic conditions is needed to ensure optimal image quality. The aim of this study was to compare the feasibility and image quality of cardiac (18)F-FDG SPECT imaging using acipimox in patients with diabetes and patients without diabetes.. Seventy patients with ischemic cardiomyopathy underwent (18)F-FDG SPECT using acipimox for the assessment of myocardial viability, followed by resting 2-dimensional echocardiography to identify dysfunctional myocardial tissue. The image quality was scored visually and quantitatively; the myocardium-to-background ratio was determined by region-of-interest analysis. The plasma concentrations of glucose and free fatty acids were determined to evaluate the metabolic conditions before and during (18)F-FDG imaging.. Thirty-four patients had diabetes mellitus; of these, 12 had insulin-dependent diabetes mellitus and 22 had non-insulin-dependent diabetes mellitus. The remaining 36 patients had no diabetes. During (18)F-FDG SPECT, no severe side effects occurred. Acipimox significantly lowered plasma levels of free fatty acids in both groups. Fifteen of 34 patients with diabetes had a plasma glucose level > 9 mmol/L, which was lowered successfully in all patients with additional insulin. Visual evaluation of the (18)F-FDG images showed good, moderate, and poor image quality in 27, 5, and 2 patients, respectively, with diabetes mellitus and in 32, 4, and 0 patients, respectively, without diabetes (P = not statistically significant). The myocardium-to-background ratio of (18)F-FDG SPECT images was comparable in patients with and without diabetes mellitus (3.1 +/- 1.0 vs. 3.5 +/- 0.9, P = not statistically significant). The type of diabetes had no influence on (18)F-FDG image quality.. (18)F-FDG SPECT metabolic imaging after acipimox is safe and practical for routine assessment of viability in patients with ischemic cardiomyopathy. Image quality is good, even in patients with diabetes, although additional insulin is sometimes needed.

Topics: Blood Glucose; Coronary Artery Disease; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Fatty Acids, Nonesterified; Feasibility Studies; Female; Fluorodeoxyglucose F18; Heart Ventricles; Humans; Male; Middle Aged; Pyrazines; Radionuclide Imaging; Radiopharmaceuticals; Ventricular Dysfunction, Left

To assess the feasibility of an intensive lipid-lowering strategy in diabetic subjects pursuing target plasma lipid levels.. Patients with diabetes mellitus (DM), Type 1 or 2, with plasma lipid levels exceeding target values (LDL-cholesterol <2.6 mmol/l, triglycerides < 1.7 mmol/l, HDL-cholesterol > 0.9 mmol/l for men and > 1.1 mmol/l for women) were eligible. After 6-12 weeks of diet and glycaemic control, lipid-lowering medication (simvastatin/gemfibrozil/acipimox) was prescribed in steps of incremental dosages and combinations for 30 weeks.. Of all eligible clinic patients, 25% initially responded and finally 12% were entered. Thirty-six patients with Type 1 and 59 with Type 2 DM were studied. Mean baseline lipid levels in Type 1 and Type 2 diabetic subjects were: LDL-cholesterol 3.6 and 3.7 mmol/l, triglycerides 1.7 and 2.2 mmol/l, HDL-cholesterol for men 1.1 and 1.0 mmol/l, and for women 1.4 and 1.2 mmol/l, respectively. All three target values were reached in 66% of the patients. LDL-cholesterol was reduced by 1.2 mmol/l in Type 1 and 1.3 mmol/l in Type 2 diabetic patients and triglycerides by 0.7 mmol/l and 1.1 mmol/l, respectively. HDL-cholesterol increased by 0.15 mmol/l and 0.34 mmol/l in men and women with Type 1 diabetes mellitus, respectively. The cholesterol-triglyceride ratio decreased significantly in VLDL in Type 1 diabetes and in IDL in Type 2 diabetes and increased significantly in HDL in Type 2 DM.. A minority of subjects eligible for intensive lipid lowering agreed to participate in a feasibility study, suggesting a potentially large compliance problem for a general lipid-lowering programme in a diabetes clinic. Nevertheless, intensive lipid lowering with drug combinations can attain the recommended target lipid levels in 66% of subjects with diabetes. With this strategy the plasma lipoprotein composition shifts towards a less atherogenic profile. Subjects with diabetes should therefore receive lipid-lowering therapy tailored to reach target levels, rather than standard dosages, in order to reduce atherogenic risk.

Topics: Adult; Aged; Blood Glucose; Cholesterol, HDL; Cholesterol, LDL; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diet; Female; Gemfibrozil; Humans; Hyperlipidemias; Hypolipidemic Agents; Lipoproteins; Male; Middle Aged; Pyrazines; Simvastatin; Triglycerides

To obtain optimal image quality in myocardial viability studies, it is recommended that 18F-fluordeoxyglucose (18F-FDG) studies be performed with hyperinsulinaemic glucose clamping. 18F-FDG imaging after oral administration of acipimox, a nicotinic acid derivative, results in comparable image quality to clamping. Twenty consecutive patients (7 with diabetes mellitus) with angiographically confirmed coronary artery disease and similar demographic/clinical profiles were randomly allocated to gated cardiac 18F-FDG-PET with a standard euglycaemic hyperinsulinaemic clamp protocol or using a combination of oral administration of acipimox and the insulin clamp technique. The image quality, expressed as the myocardial-to-blood pool activity ratio, was superior in the combined protocol compared with the insulin clamping technique alone (3.37 +/- 1.46 vs 2.27 +/- 0.62, P = 0.037). Although there were no significant differences in plasma insulin and free fatty acids concentrations between the two protocols, plasma glucose concentrations obtained with the standard protocol were elevated compared with the combined protocol (11.1 +/- 3.7 vs 6.3 +/- 3.0 mM during clamping; 10.2 +/- 3.3 vs 5.5 +/- 3.0 mM during acquisition). We conclude that gated 18F-FDG-PET imaging after oral administration of acipimox plus insulin clamping yields image quality superior to that obtained with clamping alone.

Topics: Administration, Oral; Coronary Disease; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Fluorodeoxyglucose F18; Glucose Clamp Technique; Heart; Humans; Hyperinsulinism; Hypolipidemic Agents; Infusions, Intravenous; Insulin; Male; Middle Aged; Pyrazines; Radiopharmaceuticals; Reproducibility of Results; Tomography, Emission-Computed

Myocardial and whole-body glucose metabolism was assessed in 19 insulin-dependent diabetes mellitus (IDDM) patients. A hyperglycemic clamp was performed 1) in the absence of insulin at free fatty acid (FFA) levels of 1.0 mmol/l (test 1); 2) in the absence of insulin at low FFA levels (0.1 mmol/l) by means of a lipid-lowering drug, acipimox (test 2); 3) during insulin infusion to achieve systemic levels of 400 pmol/l and FFA levels of 0.1 mmol/l (test 3); and 4) at the insulin levels of test 3 but increasing FFA to 1.0 mmol/l by means of heparin and intralipid infusion (test 4). Myocardial glucose uptake was measured by positron emission tomography (PET) and 2-[18F]fluoro-2-deoxy-D-glucose. Whole-body glucose uptake was measured in the four conditions by the glucose infusion rate during the PET scanning period. Myocardial glucose uptakes were 40.3 +/- 18.0, 395.5 +/- 139.6, 852.2 +/- 99.1, and 1,388.4 +/- 199.1 mumol.kg tissue-1.min-1 (mean +/- SD) and whole-body glucose uptakes were 10.1 +/- 2.3, 10.1 +/- 3.4, 42.8 +/- 5.8, and 30.5 +/- 5.6 mumol.kg body wt-1.min-1 during tests 1, 2, 3, and 4, respectively. Thus, in IDDM patients without coronary artery disease under the condition of hyperglycemia, an increase of myocardial glucose uptake was obtained either by lowering of FFA levels during hypoinsulinemia or by an increase in FFA levels during hyperinsulinemia. In both conditions no significant changes of whole-body glucose uptake were demonstrated.

Topics: Adult; Biological Transport, Active; Deoxyglucose; Diabetes Mellitus, Type 1; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Fluorodeoxyglucose F18; Glucose; Glucose Clamp Technique; Humans; Hypolipidemic Agents; Insulin; Male; Myocardium; Pyrazines; Somatostatin; Tomography, Emission-Computed

In type 1 diabetes mellitus (DM1), high GH basal levels and exaggerated responses to several stimuli have been described. Acipimox is an antilipolytic drug that produces an acute reduction of free fatty acids (FFA). The aim of this study was to evaluate the effect of the reduction of plasma FFA with acipimox, alone or in combination with GHRH, on GH secretion in DM1.. Six type 1 diabetic patients were studied (three women, three men), mean age of 30 +/- 2.1 years, body mass index (BMI) 23.1 +/- 1.5 kg/m2. As a control group, six normal healthy subjects of similar age, sex and weight were studied. Each patient and control received GHRH [1 microg/kg intravenously (i.v.) at min 180], acipimox (250 mg orally at min 0 and 120) and GHRH plus acipimox on three separated days. Subjects served as their own control. Blood samples were taken at appropriate intervals for determination of GH, FFA and glucose.. In control subjects, the GH area under the curve (AUC; microg/l x 120 min) was for acipimox-treated 1339 +/- 292 and 1528 +/- 330 for GHRH-induced secretion. The GH AUC after the administration of GHRH plus acipimox was 3031 +/- 669, significantly greater than the response after acipimox alone (P<0.05) or GHRH alone (P<0.05). In diabetic patients, the GH AUC was for acipimox-treated 2516 +/- 606 and 1821 +/- 311 for GHRH-induced secretion. The GH AUC after the administration of GHRH plus acipimox was 7311 +/- 1154, significantly greater than the response after acipimox alone (P<0.05) or GHRH alone (P<0.05). The GH response after acipimox was increased in diabetic when compared with normal (P<0.05), with a GH AUC of 1339 +/- 292 and 2515 +/- 606 for normal subjects and diabetic patients, respectively. The GH response after acipimox plus GHRH was increased in diabetic when compared with normal (P<0.05), with a GH AUC of 3031 +/- 669 and 7311 +/- 1154 for normal subjects and diabetic patients, respectively. The administration of acipimox induced a FFA reduction during the entire test.. Reduction of free fatty acids with acipimox is a stimulus for GH secretion in DM1. The combined administration of GHRH plus acipimox induces a markedly increased GH secretion in type 1 diabetic patients when compared with normal subjects. These data suggest that patients with DM1 exhibit a greater GH secretory capacity than control subjects, despite the fact that endogenous FFA levels seems to exert a greater inhibitory effect on GH secretion in these patients.

Topics: Adult; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Fatty Acids, Nonesterified; Female; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Hypolipidemic Agents; Male; Pyrazines; Somatomedins

It is controversial as to whether ketone bodies are utilized by the human brain as a fuel alternative to glucose during hypoglycaemia. To clarify the issue, we studied 10 normal volunteers during an experimental hypoglycaemia closely mimicking the clinical hypoglycaemia of patients with Type 1 (insulin-dependent) diabetes mellitus or insulinoma. Hypoglycaemia was induced by a continuous infusion of insulin (0.40 mU.kg-1.min-1 for 8 h, plasma insulin approximately 180 pmol/l) which decreased the plasma glucose concentration to approximately 3.1 mmol/l during the last 3 h of the studies. Subjects were studied on two occasions, i.e. spontaneous, counterregulatory-induced post-hypoglycaemic increase in 3-beta-hydroxybutyrate (from approximately 0.2 to approximately 1.1 mmol/l at 8 h), or prevention of post-hypoglycaemic hyperketonaemia (plasma beta-hydroxybutyrate approximately 0.1 mmol/l throughout the study) after administration of acipimox, a potent inhibitor of lipolysis. In the latter study, glucose was infused to match the hypoglycaemia observed in the former study. The glycaemic thresholds and overall responses of counterregulatory hormones, symptoms (both autonomic and neuroglycopenic), and deterioration of cognitive function (psychomotor tests) were superimposable in the control study in which ketones increased spontaneously after onset of hypoglycaemic counterregulation, as compared to the study in which ketones were suppressed (p = NS). The fact that responses of counterregulatory hormones, symptoms and deterioration in cognitive function were not exaggerated when posthypoglycaemic hyperketonaemia was prevented, indicate that during hypoglycaemia, the counterregulatory-induced endogenous hyperketonaemia does not provide the human brain with an alternative substrate to glucose. Thus, it is concluded that during hypoglycaemia, endogenous hyperketonaemia does not contribute to brain metabolism and function.

Topics: 3-Hydroxybutyric Acid; Adult; Alanine; Brain; Cognition; Diabetes Mellitus, Type 1; Female; Glycerol; Homeostasis; Hormones; Humans; Hydroxybutyrates; Hypoglycemia; Hypolipidemic Agents; Insulin; Insulinoma; Ketone Bodies; Lactates; Lipolysis; Male; Pancreatic Neoplasms; Pyrazines; Reaction Time