Untreated Diabetic Patients Research Articles

Peroxisome proliferator–activated receptor γ agonist improves arterial stiffness in patients with type 2 diabetes mellitus and coronary artery disease

Arterial stiffness is an independent risk factor for cardiovascular events in diabetic patients, and it can be assessed by measuring pulse wave velocity (PWV). We investigated the degree of arterial stiffness in diabetic patients with coronary artery disease (CAD) and the effect of the proliferator-activated receptor γ (PPAR- γ) agonist rosiglitazone on arterial stiffness in the potential mechanism of anti-arteriosclerosis in patients with type 2 diabetes mellitus and CAD. The 123 participants were divided into 3 groups: healthy controls (n = 36), diabetic patients (n = 41), and diabetic patients with CAD (n = 46). Forty-six diabetic patients with CAD were randomly divided into 2 groups: untreated diabetic patients with CAD and diabetic patients with CAD treated with 4 mg/d of rosiglitazone (n = 25) for 12 weeks. Pulse wave velocity was measured before treatment and at 12-week follow-up. Baseline PWV was significantly higher in patients with diabetes, diabetes and CAD, and diabetes and CAD with treatment as compared with the healthy control group (1633 ± 37.3, 1669 ± 53.8, 1615 ± 44.4, and 1360 ± 39.9 cm/s, respectively, P < .001). Pulse wave velocity in the rosiglitazone-treated group was significantly reduced, from 1615 ± 44.4 to 1525 ± 43.1 cm/s, after 12-week treatment, Furthermore, PWV was significantly decreased in the rosiglitazone-treated group compared with untreated group after 12 weeks (1525 ± 43.1 and 1670 ± 41.3 cm/s, respectively). Pulse wave velocity in the untreated group did not differ from baseline levels after 12 weeks. In addition, plasma C-reactive protein level was decreased significantly in the rosiglitazone-treated group compared with values at baseline and for the untreated group after 12 weeks (0.73 ± 0.09, 1.71 ± 0.24, and 1.33 ± 0.29 mg/L, respectively). Plasma level of monocyte chemoattractant protein 1 was decreased in the rosiglitazone group compared with the level at baseline (392 ± 42 and 273 ± 40 pg/mL, respectively). Moreover, the decrease in PWV was associated linearly both with improved homeostasis model assessment of insulin resistance and with decreased C-reactive protein level after PPAR- γ agonist treatment. In conclusion, PPAR- γ agonist rosiglitazone treatment may significantly decrease arterial stiffness in diabetic patients with CAD. Proliferator-activated receptor γ agonists may play an important role in protecting against arteriosclerosis by normalizing the metabolic disorders and depressing chronic inflammation of the vascular system in patients with type 2 diabetes mellitus and serious vascular disease.

Determination of prothrombin time and activated partial thromboplastin time in newly diagnosed untreated cases of type-2 diabetes mellitus at the University of Nigeria Teaching Hospital, Enugu

Background: Diabetes Mellitus is leading endocrine disorder of global interest. It is of multifactorial aetiology. Methods: Coagulation status of newly diagnosed and untreated diabetic patients from the Diabetes Medical out-patient Department of University of Nigeria Teaching Hospital, Ituku Ozalla, Enugu State, Nigeria was studied. Seventy (70) newly diagnosed and untreated diabetic patients aged 20 – 60 years and 70 age and sex-matched non-diabetic controls were randomly selected after screening biochemically for diabetes mellitus, using standard glucometer. The 1997 World Health Organisation criteria for diagnosis of diabetes mellitus were used. Results: Prothrombin Time (PT), and Activated Partial Thromboplastin Time (APTT) were determined using Dacie and Lewis method. Body Mass Index (BMI) was also estimated. Only PT and BMI, showed statistically significant differences (PL 0.05) when the male mean diabetic values were compared with jthose of the female diabetic patients. Also, APTT, Fasting Blood Sugar (FBS) and BMI revealed statistically significant differences (P Keywords : Prothrombin time; Activated partial Thromboplastin time; Newly Diagnosed Untreated; Type 2 Diabetes Mellitus Journal of College of Medicine Vol. 12 (1) 2007: pp.30-34

Homocysteine-lowering vitamin B treatment decreases cardiovascular events in hemodialysis patients

In Italy, the mortality rate of hemodialysis patients is approximately 14% per year. Cardiovascular disease is the most important cause of morbidity and mortality in hemodialysis patients. High plasma homocysteine levels are commonly detected in these patients, but hyperhomocysteinemia and cardiovascular mortality are not always strictly correlated. The Dialysis Outcomes and Practice Pattern Study (DOPPS) showed a direct association between regular use of water-soluble vitamins and lower cardiovascular mortality. We recently performed a long-term prospective trial to study the effects of folic acid therapy on cardiovascular events in hemodialysis patients. We observed not only a lower rate of combined cardiovascular events in patients treated with folate, but also a direct correlation between hyperhomocysteinemia and cardiovascular morbidity. On the contrary, the distribution of deaths was similar in treated and untreated patients, because, almost certainly, sudden death is not always due to atherosclerotic events, and non-cardiovascular deaths, such as cachexia, septicemia and malignancy were characterized by low levels of homocysteine, which may be, in addition, a nutritional index similar to albumin and protein catabolic rate. As it is known that diabetic hemodialysis patients have a higher mortality rate, but lower homocysteine levels as compared to non-diabetic patients, we performed an equal allocation of diabetic patients in treated and untreated groups. We observed a similar homocysteine reduction rate in diabetic patients as compared to non-diabetic patients, and a trend towards a lower rate of composite cardiovascular events in treated diabetic patients as compared to untreated diabetic patients. To summarize, the strong relationship between homocysteine and nutritional, inflammatory markers may hide its association with cardiovascular disease. Homocysteine-lowering vitamin B therapy may lower cardiovascular events in dialysis patients. It is mandatory to perform large prospective trials to confirm our results.

Intestinal microsomal triglyceride transfer protein in type 2 diabetic and non-diabetic subjects: The relationship to triglyceride-rich postprandial lipoprotein composition

Background Microsomal triglyceride transfer protein (MTP) is responsible for the assembly of the triglyceride-rich lipoproteins (TRLs) and is increased in diabetic animal models. Human intestinal MTP expression has not been previously reported. This study examined the relationship between intestinal MTP gene expression and postprandial TRL composition in diabetic and non-diabetic subjects. Since the MTP promoter region has a sterol response element the effect of statins on intestinal MTP mRNA was analysed. Methods Twenty-seven diabetic and 24 non-diabetic subjects were examined. Duodenal biopsies were taken during gastroscopy and MTP mRNA was measured by RNase protection assay. Postprandial lipoprotein composition was determined. Results Diabetic subjects had significantly higher MTP mRNA than non-diabetic subjects. Statin therapy was associated with lower MTP mRNA in both groups. In the untreated diabetic patients compared to the untreated non-diabetic patients MTP mRNA was 25.0 ± 25.1 amol/μg versus 13.1 ± 5.6 amol/μg total RNA ( p < 0.05). In the statin-treated diabetic group compared to statin-treated non-diabetic group MTP mRNA was 17.7 ± 8.6 amol/μg versus 5.8 ± 4.1 amol/μg total RNA ( p < 0.05). In the whole group there was a positive correlation between the MTP mRNA and postprandial chylomicron cholesterol/B48 ( r = 0.36, p < 0.01). Conclusions This is the first study to demonstrate increased MTP expression in diabetic subjects. MTP mRNA expression was lower in statin-treated patients confirming the suggestion that the insulin and sterol response elements of the MTP gene are important regulators of MTP transcription in diabetes. Our results show that MTP plays a central role in regulating the cholesterol content of the chylomicron particle.

Management and short-term outcome of diabetic patients hospitalized for acute myocardial infarction: results of a nationwide French survey

To compare management and short-term outcome of diabetic and non-diabetic patients hospitalized for acute myocardial infarction. This was a prospective epidemiological survey. All patients admitted in coronary care units in France in November 2000 for confirmed acute myocardial infarction were eligible to enter the study. Of the 2320 patients recruited from 369 centers, 487 were diabetic (21%). Compared to non-diabetic patients, diabetic patients were 5 years older, more often female, obese and hypertensive; they had more often a history of cardiovascular disease; they had a lower ejection fraction and worse Killip class. Reperfusion therapy was less frequent among diabetic patients (39% versus 51%; p=0.0001), as was the use of beta-blockers (61% versus 72%; p=0.0001), aspirin (83% versus 89%; p=0.0001) and statins (52% versus 60%; p=0.001) during hospitalization. Conversely, the use of ACE-inhibitors was more frequent (54% versus 44%; p=0.0001). 58% of diabetic patients received insulin during hospitalization. Twenty-eight-day mortality was 13.1% in diabetic patients and 7.0% in non-diabetic patients (risk ratio: 1.87; p=0.001). Diabetes remained associated with increased mortality after adjustment for relevant risk factors including age and ejection fraction (risk ratio: 1.51; p=0.07). In patients treated with antidiabetic drugs (chiefly sulfonylureas) before admission, 28-day mortality was 10.4% compared with 19.9% in diabetic patients on diet alone or untreated (p=0.005). Despite higher cardiovascular risk and worse prognosis, in-hospital management of diabetic patients with acute myocardial infarction remains sub-optimal. Patients previously treated with antidiabetic drugs including sulfonylureas had a better prognosis than untreated diabetic patients.

Alterations in the growth hormone-insulin-like growth factor axis in insulin dependent diabetes mellitus.

The growth hormone (GH)-insulin-like growth factor (IGF) axis and insulin are major anabolic effectors in promoting weight gain and linear growth. These two anabolic systems are interlinked at many levels, thus abnormalities in one of these systems effect the other causing disordered metabolic homeostasis. Insufficient portal insulinization in insulin dependent diabetes mellitus (IDDM) results in hepatic GH resistance and increased production of IGF-binding proteins-1 (IGFBP-1) and IGFBP-2. GH resistance is reflected by decreased hepatic IGF-I production. In addition, changes in other GH-dependent proteins are also observed in IDDM. Increased proteolysis of IGFBP-3 results in reduction of intact IGFBP-3. Serum ALS levels are also slightly diminished in untreated diabetic patients. Hepatic resistance to GH is, at least in part, caused by diminished GH receptors as reflected by diminished circulating GHBP levels. In addition, there is also evidence from experimental and human studies suggesting post-receptor defect(s) in GH action. As a result of these changes, circulating total and free IGF-I levels are decreased during insulinopenia. Lack of negative feed-back effect of IGF-I on GH secretion causes GH hypersecretion which increases hyperglycemia by decreasing sensitivity to insulin. GH hypersecretion in poorly controlled diabetic patients may play a role in the pathogenesis of diabetic vascular complications. Most of these abnormalities in the GH-IGF axis in diabetes are reversed by effective insulinization of the patient. Addition of IGF-I treatment to insulin in adolescents with IDDM allows correction of GH hypersecretion, improves insulin sensitivity and glycemic control, and decreases insulin requirements. The effect of IGF-I treatment on diabetic complications has yet to be seen.

Diabetic dyslipidemia

Usual risk factors for coronary artery disease account for only 25–50% of increased atherosclerotic risk in diabetes mellitus. Other obvious risk factors are hyperglycemia and dyslipidemia. However, hyperglycemia is a very late stage in the sequence of events from insulin resistance to frank diabetes, whereas lipoprotein abnormalities are manifested during the largely asymptomatic diabetic prodrome and contribute substantially to the increased risk of macrovascular disease. The insulin-resistant diabetes course affects virtually all lipids and lipoproteins. Chylomicron and very-low-density lipoprotein (VLDL) remnants accumulate, and triglycerides enrich high-density lipoprotein (HDL) and low-density lipoprotein (LDL), leading to high levels of potentially atherogenic particles and low levels of HDL cholesterol. Hyperglycemia eventually impairs removal of triglyceride-rich lipoproteins, the accumulation of which accentuates hypertriglyceridemia. As triglycerides increase—still within the so-called normal range—abnormalities in HDL and LDL became more apparent. Thus, when triglycerides are >200 mg/dL, LDL particles are small and dense (when they are <90 mg/dL, the particles are of the large, buoyant variety). The atherogenicity of small, dense LDL particles is attributed to their increased susceptibility to oxidation, but in many patients they may be a marker for insulin resistance or the presence of atherogenic VLDL. Hypertriglyceridemia is associated with atherosclerosis because (1) it is a marker for insulin resistance and atherogenic metabolic abnormalities; and (2) the small size of triglyceride-enriched lipoproteins enables them to infiltrate the blood vessel wall where they are oxidized, bind to receptors on macrophages, and ingested, leading to the development of the atherosclerotic lesion. Various studies (primary prevention with gemfibrozil: Helsinki Heart Study; secondary prevention with simvastatin and pravastatin: Scandinavian Simvastatin Survival Study [4S] and Cholesterol and Recurrent Events [CARE], respectively) have demonstrated that lipid-lowering therapy in type 2 diabetes is effective in decreasing the number of cardiac events. Risk reduction was 22% to 50% (statins) and ∼65% (fibrate) relative to placebo. It was also noted (in 4S and CARE) that the risk of major coronary events in untreated diabetic patients was 1.5–1.7-fold greater than in untreated nondiabetic patients. Although gemfibrozil (fibric acid derivative) is more effective in decreasing triglycerides and increasing HDL cholesterol in diabetic patients than the statins, it does not change and may even increase LDL-cholesterol levels (fenofibrate may be an exception, decreasing LDL cholesterol by 20–25% in some studies). However, gemfibrozil does increase LDL particle size. Nevertheless, the statins are the current lipid-lowering drugs of choice because the change in LDL-cholesterol-to-HDL-cholesterol ratio is better than with gemfibrozil. Moreover, the diabetic patient may be more likely to benefit from statin therapy than the nondiabetic patient. It should be noted that, in theory, nicotinic acid can correct or improve all lipid or lipoprotein abnormalities in patients with type 2 diabetes. Unfortunately, it is relatively contraindicated because it causes insulin resistance and may precipitate or aggravate hyperglycemia (in addition to its other well-known side effects such as flushing, gastric irritation, development of hepatotoxicity, and hyperuricemia). It is unknown at present whether newer formulations such as once-daily Niaspan may be better tolerated in diabetes. In any case, most patients with type 2 diabetes have risk factors for coronary artery disease and qualify for aggressive LDL cholesterol–lowering therapy. At the same time, it is presently unknown whether improved glycemic control decreases coronary artery disease risk in such patients.

A Commentary on 10 Years of Aldose Reductase Inhibition for Limited Joint Mobility in Diabetes

This investigation examines the clinical response to long-term treatment of the diabetic syndrome of limited joint mobility (LJM) using an aldose reductase inhibitor (ARI) in comparison to historical controls, and proposes a potential role of aldose reductase (AR) genotype and expression in the clinical response to ARI. Clinical parameters, including quantitative hand movement and electromyogram, were followed over a decade of continuous ARI treatment with sorbinil (400 mg/day) in two patients with insulin-dependent diabetes mellitus (IDDM) and severe compromising LJM, and compared to the published 10-year prospective investigation of untreated IDDM diabetic patients with LJM. Both subjects were homozygous for the Z-2 AR allele (A-C)23 that has been linked with microvascular complications of DM. Cellular AR mRNA/β-actin ratios for both treated patients while on ARI therapy were approximately one-half the value observed in untreated patients with the complications of nephropathy or neuropathy. This is the longest reported experience of ARI intervention for any diabetic complication, documenting sustained correction of LJM, lack of side effects, and a potential molecular basis for the therapeutic response.

Iloprost decreases urinary albumin excretion rate in patients with diabetic nephropathy

We conducted an open clinical trial to determine whether administration of iloprost, a stable prostacyclin analog, has any effect on urinary albumin excretion and other parameters associated with non-insulin-dependent diabetes mellitus (NIDDM) patients. Twenty-three NIDDM patients with nephropathy were divided into groups A and B which were matched in terms of sex, age, duration of diabetes and blood glucose control. After 2 weeks of observation, 11 patients in group A received an intravenous infusion of iloprost (10 μg at a rate of 0.075 μg/kg per h) once daily for 2 weeks, while 12 untreated diabetic patients in group B served as controls. In group A, iloprost significantly reduced the urinary albumin excretion rate, the urinary albumin-creatinine ratio and N-acetyl-β- d-glucosaminidase without decreasing creatinine clearance during the treatment period ( P < 0.05, respectively). However, none of these parameters changed significantly in group B. Urinary β 2-microglobulin, blood pressure, heart rate, serum electrolytes, BUN and serum creatinine were not significantly altered by iloprost during the treatment period. Side effects associated with iloprost were mild and could be ameliorated by slowing the infusion rate. We conclude that iloprost appears to be safe and has an apparent effect on the urinary albumin excretion rate and N-acetyl-β- d-glucosaminidase.

Effect of insulin on serum lipids in relation to nutritional status in diabetics

Serum levels of cholesterol, triglyceride, free fatty acid (FFA) and high density lipoprotein (HDL) cholesterol were studied in 10 undernourished and 10 better nourished diabetic patients at different periods of insulin treatment and in non-diabetic controls. Serum concentrations of cholesterol, triglyceride and FFA were significantly higher in untreated diabetic patients than in control but the elevated lipid levels gradually shifted towards normal on insulin treatment. The HDL cholesterol, on the other hand, was significantly lower in untreated diabetic subjects than those in controls and the HDL cholesterol also gradually modified on insulin therapy. However, the improvement of all the lipid parameters on insulin treatment was somewhat delayed in undernourished compared to those of better nourished diabetics. These results, therefore, suggest that malnutrition interferes with the serum lipid improvement in diabetics on insulin treatment and may make them more prone to develop vascular complications.

Human Placental Insulin Binding in Normal and Well-Controlled Diabetic Patients

Previous studies of insulin binding to placentas of both insulin-dependent and untreated gestational diabetic patients have described placentas from diabetics to contain fewer insulin receptors than placentas from nondiabetic gravidas. However, these studies were done using membrane fractions prepared from the placentas and at a time when adequacy of antepartum glycemic control in the diabetic patients was not routinely evaluated by self blood sugar measurement or hemoglobin A1 assay. The current study compares specific 125I-insulin binding in vitro to intact placental villi from 15 normal patients with insulin binding to intact villi obtained from 15 insulin-dependent diabetic mothers whose fasting and postprandial blood sugars and hemoglobin A1 levels were maintained in a range normal for term pregnancy. We demonstrate that insulin binding to intact placental villi is the same in this group of diabetic patients as in the nondiabetic patients.

Endogenous insulin secretion in newly diagnosed diabetic patients in Saudi Arabia

Diabetes mellitus is a major health problem in Saudi Arabia. The evaluation of endogenous insulin secretion at diagnosis has not yet been studied in this population. We have therefore studied fasting and post-glucagon stimulation levels of glucose, insulin and C-peptide in 216 newly diagnosed untreated diabetic patients. The mean ± SD fasting insulin and C-peptide levels were 14.0 ± 1.8 μU/ml and 1.8 ± 0.4 ng/ml, while post-glucagon stimulation levels were 21.1 ± 3 μU/ml and 2.4 ± 0.4 ng/ml. There were significant post-stimulatory increment levels for insulin, from 4.9 to 13.7 μU/ml, and C-peptide from 0.2 to 1.3 ng/ml ( P < 0.001). Such increments did not affect specified age distribution. We found a significant correlation between the fasting levels and post-stimulation levels of C-peptide and insulin. Obesity correlated with higher basal and post-stimulation levels of both hormones ( r = 0.67, P < 0.001). The mean ± SD fasting insulin and C-peptide levels were 18.5 ± 9.1 μU/ml and 2.4 ± 0.8 ng/ml for obese patients and 11.5 ± 5.1 μU/ml and 1.9 ± 1.1 ng/ml for non-obese patients. The type of diabetes among the Saudi adult diabetic patients studied is characterized by high basal C-peptide and insulin levels which increase significantly with stimulation, suggesting diminished but present endogenous B-cell function.

Prevalence of vascular complications in untreated diabetics with obesity during an 18 year period

Prevalence of vascular complications in newly diagnosed untreated diabetic patients with obesity was studied over a period of 18 years. A total of 742 patients including 241 subjects with obesity (BMI > 25) were analyzed. Obese patients showed higher serum cholesterol and triglyceride and lower HDL-cholesterol levels than non-obese patients. Average prevalence of obesity is shown to be 32.5% with higher prevalence in women (37.8%) than in men (28.3%, P < 0.01). No definite change is found in yearly prevalence throughout the observation period. Ischemic ECG findings and hypertension were observed more frequently in obese (35.8% and 34.9%, respectively) than in non-obese (25.2%, P < 0.02; 24.5%, P < 0.01, respectively) subjects, while diabetic retinopathy was less in obese patients (P < 0.05). The prevalence of proteinuria was almost the same in obese and non-obese groups. These results coincide with the general concept that obesity may be responsible for the development of macroangiopathy in diabetes mellitus.

Increased Proximal Tubular Sodium Reabsorption in Hypertensive Patients with Type 2 Diabetes

Hyperinsulinaemia and sodium retention have been studied in 22 Type 2 diabetic patients (10 normotensive, 12 hypertensive) and 10 normal control subjects matched for age, sex, and body mass index. Exchangeable sodium was similar in the three groups. Plasma renin activity and plasma angiotensin II were lower in both groups of diabetic patients than in the normal control subjects (p less than 0.01). Plasma atrial natriuretic peptide was increased in the hypertensive patients (7.3 +/- 1.1 vs normotensive 4.7 +/- 1.1 pmol l-1 and control 4.0 +/- 0.2 pmol l-1, p less than 0.01). Fractional lithium clearance, a measure of sodium clearance from the proximal tubule, was decreased (18.5 +/- 1.4, p less than 0.01) and fractional excretion of sodium in the distal tubule was increased (6.66 +/- 0.66, p less than 0.01) in untreated hypertensive diabetic patients compared with both normotensive diabetic patients (25.3 +/- 1.6 and 3.96 +/- 0.52 respectively) and normal control subjects (25.2 +/- 2.9 and 3.31 +/- 0.38, respectively). Fasting serum insulin was higher in hypertensive than in normotensive diabetic patients (18.5 +/- 3.0 vs 10.7 +/- 1.1 mU l-1, p less than 0.01) and higher in both groups than in normal control subjects (5.6 +/- 0.1 mU l-1, both p less than 0.01). Creatinine clearance was higher in both groups of diabetic patients than in normal control subjects (p less than 0.05). Thus there appears to be increased proximal renal tubular sodium reabsorption in these hypertensive Type 2 diabetic patients, matched by a reduction in distal sodium reabsorption so that net sodium excretion was maintained. This was associated with fasting hyperinsulinaemia.

Quantitation of forearm glucose and free fatty acid (FFA) disposal in normal subjects and type II diabetic patients: evidence against an essential role for FFA in the pathogenesis of insulin resistance.

This study was designed to quantitate glucose and FFA disposal by muscle tissue in patients with type II diabetes and to investigate the relationship between FFA metabolism and insulin resistance. The forearm perfusion technique was used in six normal subjects and two groups of normal weight diabetic patients, i.e. untreated (n = 8) and insulin-treated (n = 6). The latter received 2 weeks of intensive insulin therapy before the study. Plasma insulin levels were raised acutely [950-1110 pmol/L) (130-150 microU/mL)], while the blood glucose concentration was clamped at its basal value [4.9 +/- 0.1 (+/- SE) mmol/L in the normal subjects, 5.7 +/- 0.5 in the insulin-treated diabetic patients, and 5.5 +/- 0.3 in the untreated diabetic patients] by a variable glucose infusion. During the control period, arterial FFA concentrations were similar in the three groups, and they decreased to a comparable extent (less than 0.1 mmol/L) in response to insulin infusion. During the control period, the mean forearm FFA uptake was 2.5 +/- 0.5 mumol/L.min in the normal subjects, 2.9 +/- 0.5 in the insulin-treated patients, and 2.1 +/- 0.5 in the untreated diabetic patients. During the insulin infusion, FFA uptake was profoundly suppressed to similar levels in the normal subjects (0.9 +/- 0.1 mumol/L.min), the insulin-treated diabetic patients (1.1 +/- 0.3), and the untreated diabetic patients (0.9 +/- 0.1; P less than 0.001). Forearm glucose uptake was similar in the three groups during the control period. It increased during the insulin infusion, but the response in both diabetic groups was less than that in the normal subjects. The total amounts of glucose taken up by the forearm during the study period were 5.2 +/- 0.7, 2.6 +/- 0.5, and 2.1 +/- 0.6 mmol/L.min in the normal subjects, the insulin-treated diabetic patients, and the untreated diabetic patients, respectively (P less than 0.01). We conclude that 1) insulin-mediated glucose uptake by forearm skeletal muscle is markedly impaired in type II diabetes and improves only marginally after 2 weeks of intensive insulin therapy; 2) in contrast, no appreciable abnormality in forearm FFA metabolism is demonstrable in insulin-treated type II diabetic patients; and 3) FFA do not contribute to the insulin-treated skeletal muscle insulin resistance that occurs in patients with type II diabetes mellitus.

Intracellular insulin processing is altered in monocytes from patients with type II diabetes mellitus.

We studied total cell-associated A14-[125I]insulin radioactivity (including surface-bound and internalized radioactivity), insulin internalization, and its intracellular degradation at 37 C in monocytes from nonobese type II untreated diabetic patients (n = 9) and normal subjects (n = 7). Total cell-associated radioactivity was decreased in diabetic patients [2.65 +/- 1.21% (+/- SD) vs. 4.47 +/- 1.04% of total radioactivity; P less than 0.01]. Insulin internalization was also reduced in diabetic patients (34.0 +/- 6.8% vs. 59.0 +/- 11.3% of cell-associated radioactivity; P less than 0.01). Using high performance liquid chromatography six intracellular forms of radioactivity derived from A14-[125I] insulin were identified; 10-20% of intracellular radioactivity had approximately 300,000 mol wt and was identified as radioactivity bound to the insulin receptor, and the remaining intracellular radioactivity included intact A14-[125I]insulin, [125I]iodide, or [125I]tyrosine, and three intermediate compounds. A progressive reduction of intact insulin and a corresponding increase in iodine were found when the incubation time was prolonged. Intracellular insulin degradation was reduced in monocytes from diabetic patients; intracellular intact insulin was 65.6 +/- 18.1% vs. 37.4 +/- 18.0% of intracellular radioactivity (P less than 0.01) after 2 min and 23.6 +/- 22.3% vs. 3.9 +/- 2.3% (P less than 0.01) after 60 min in diabetic patients vs. normal subjects, respectively. In conclusion, 1) human monocytes internalize and degrade insulin in the intracellular compartment in a stepwise time-dependent manner; and 2) in monocytes from type II diabetic patients total cell-associated radioactivity, insulin internalization, and insulin degradation are significantly reduced. These defects may be related to the cellular insulin resistance present in these patients.

Haemoglobin A 1c levels in normal and diabetic pregnancies

Serial measurements of the HbA 1c levels were performed during pregnancy in 4 groups of patients attending Antenatal Clinics: 36 normal pregnancies; 16 prenancies in established insulin-dependent diabetic patients; 9 patients with gestational diabetes diagnosed during that pregnancy; and 21 patients who had been diagnosed as having gestational diabetes in at least one previous pregnancy. In the normal pregnancy HbA 1c levels showed a small but significant increase from the end of the first trimester to delivery despite blood glucose levels remaining constant throughout. In the insulin-dependent and gestational diabetic patients, blood glucose levels remained significantly higher than in the normal throughout pregnancy but only in insulin-dependent diabetic patients and the newly diagnosed untreated gestational diabetic patients were the HbA 1c levels significantly higher than in the normal. In those patients who had previous pregnancies complicated by gestational diabetes, blood glucose levels were significantly higher than in the normal but HbA 1c levels were not. This dissociation between blood glucose and HbA 1c levels in gestational diabetic pregnancies in particular limits the value of HbA 1c levels in monitoring antidiabetic treatment in such pregnancies.

Impaired insulin action in newly diagnosed type 1 (insulin-dependent) diabetes mellitus.

Hepatic and peripheral insulin sensitivity were investigated in five newly diagnosed Type 1 (insulin-dependent) diabetic subjects before and after 1 week of twice daily insulin therapy. Eight weight-matched control subjects were also studied. Hepatic glucose production and glucose utilization were measured basally and during two sequential 2-h insulin (25 and 40 mU X kg-1 X h-1)/ glucose infusion periods. In the untreated hyperglycaemic diabetic patients hepatic glucose production was 16.3 +/- 2.6, 8.1 +/- 1.1 and 3.6 +/- 2.8 mumol X kg-1 X min-1 respectively for each of the three periods (mean +/- SEM), and fell with treatment to 12.5 +/- 1.4, 0.5 +/- 0.5 and 0.5 +/- 0.5 mumol X kg-1 X min-1. Hepatic glucose production for normal subjects was 13.4 +/- 0.7, 2.3 +/- 0.8 and less than 0.1 mumol X kg-1 X min-1. Glucose utilization was 12.7 +/- 1.4, 18.2 +/- 0.7 and 22.1 +/- 3.4 mumol X kg-1 X min-1 before treatment in the diabetic subjects, and 11.8 +/- 1.7, 20.9 +/- 3.3 and 30.1 +/- 3.6 after treatment. These values compare with those in the euglycaemic control subjects (13.4 +/- 0.7, 18.7 +/- 1.6 and 36.3 +/- 2.7 mumol X kg-1 X min-1). The pre-treatment metabolic clearance rate of glucose in all diabetic studies with insulin levels greater than 30 mU/l was 2.6 +/- 0.4 and rose to 3.9 +/- 0.5 ml X kg-1 X min-1 following insulin therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Levels of HbAi and Red-cell 2, 3 DPG in Newly Discoverd or Untreated Diabetic Patients with and without Ketoacidosis

Levels of HbAi and Red-cell 2, 3 DPG in Newly Discoverd or Untreated Diabetic Patients with and without Ketoacidosis

Nerve Conduction Abnormalities in Untreated Maturity-Onset Diabetes: Relation to Levels of Fasting Plasma Glucose and Glycosylated Hemoglobin

The role of metabolic abnormalities in the development of diabetic neuropathy is controversial. To investigate the influence of hyperglycemia on nerve conduction, we studied 20 untreated maturity-onset diabetic patients and 23 normal control subjects of similar age. Nerve conduction velocity of motor (median, peroneal, and tibial) and sensory (median and sural) nerves in diabetic patients was significantly slowed and H-reflex latency time prolonged. Levels of fasting plasma glucose in diabetic subjects were correlated with slowed motor conduction velocity of the median, peroneal, and tibial nerves but not with sensory nerve conduction velocities. Levels of glycosylated hemoglobin, an index of long-term glycemia, were correlated with slowing of peroneal motor conduction velocity in diabetic patients. These associations could not be explained by patient age or duration of diabetes. These findings suggest that the degree of hyperglycemia of untreated maturity-onset diabetes contributes to the motor nerve conduction abnormalities in this disease.