Obese NIDDM Research Articles

Assessment of Serum Insulin and VASPIN Levels Among Type 2 Diabetes Mellitus Patients with or Without Obesity: A Cross-sectional Analytical Study.

A collection of diverse conditions together referred to as diabetes mellitus frequently manifest as periods of hyperglycemia and glucose intolerance, which can be caused by insufficient insulin, improper insulin action, or both. A medical condition known as obesity is the accumulation of excess body fat to the point that it may be harmful to one's health. It has been determined that the adipokine vaspin (visceral adipose tissue-derived serpin A12) belongs to the family of serine protease inhibitors. Insulin, a polypeptide hormone, is released by the pancreatic beta cells. This hormone is both anti-catabolic and anabolic. Insulin decreases blood glucose levels by preventing its synthesis and encouraging its storage and use. In total, 125 male and female participants of various ages participated in the current study. They included 25 healthy controls, 50 non-obese and 50 obese non-insulin-dependent diabetes mellitus patients, who visited the MDM Hospital's outpatient clinic in Jodhpur, Rajasthan. Commercially available reagents and kits were utilized for the analysis of serum insulin and vaspin samples. Standard statistical tools were utilized to evaluate the parameters. When results were compared with healthy participants and non-obese NIDDM subjects, obese NIDDM subjects showed statistically significant higher fasting serum insulin and serum vaspin levels (P < 0.0001). Our study's conclusions demonstrated a strong correlation between blood insulin and vaspin levels and diabetes and obesity. Vaspin has a positive impact on insulin resistance, obesity, type 2 diabetes, and metabolic syndrome. It also enhances glucose tolerance and insulin sensitivity, reducing diabetes complications. This novel biomarker has the potential to enhance diabetes mellitus outcomes by facilitating prompt diagnosis, improved management, and reduction of complications.

Effect of a chromium‐fructooligosaccharide complex on glycemic parameters in obese and obese‐NIDDM rats

The incidence and odds ratio of obesity and Type 2 diabetes, a common sequela of obesity, are increasing in incidence to the point of becoming epidemic in Western society. To determine the potential beneficial effects of a chromium‐fructooligosaccharide complex (FCC) on glycemic responses of male obese and obese NIDDM rats, groups of 3 ‐ 4 month old lean and obese LA/Ntul//‐cp and SHR/Ntul//‐cp rats (NIDDM‐rats, n= 6 rats/group) reared normally on Purina #5012 chow from the time of weaning, were subjected to an oral glucose tolerance (OGT) after a brief 4‐hour fast. A second group of NIDDM rats (n=5) aged one year were also administered the OGT and FCC challenges. NIDDM rats develop IGT by adolescence and renal disease, cataracts, and impaired nerve conduction velocity typical of DM by adulthood. Animals were administered a glucose solution equivalent to 2.5 grams/kg BW via intragastric gavage, or the same glucose plus the FCC (2.5 g/kg BW, containing 200µg Cr and 2.25 mg/serving) or the FCC alone over a brief (1‐2 minute) duration. Measures of blood glucose (BG) were determined at 30‐minute intervals from zero to +120 minutes post gavage via tail bleeding, and the area under the curve (AUC) of each group determined. Final body weights (BW) of obese were greater than lean (p=0.05), and obese‐NIDDM &gt; Obese rats (p=&lt;0.05) and increased in NIDDM rats with older age. OGT of lean rats remained normal throughout, and FCC resulted in minor decreases in AUC and in BG concentrations at all time points (p= n.s.) The OGT of obese rats demonstrated significant increases in BG at +60, +90‐, and +120‐minutes post gavage but remained non‐diabetic, and FCC decreased the glycemic increase and AUC by ~50%, similar to the glycemic response off lean littermates. The OGT of young NIDDM was significantly impaired and FCC resulted in a 32% reduction in the AUC. The OGT and AUC of OLD NIDDM rats was greater than in young rats and was decreased by 25% with FCC. OGT and OGG+FCC were similar at both ages in NIDDM rats. These results are consistent with an FCC‐mediated improvement in glycemic control in congenic animal models for obesity and obesity+NIDDM and suggest that the FCC complex may be a useful nutraceutical adjunct in the dietary treatment of obesity and other glucose intolerant states as they occur in man and animals.

O-48: TNFα and insulin sensitivity in humans: effects in vivo of antibody blockade in obese NIDDM patients and in vitro upon human cultured myotubes

O-48: TNFα and insulin sensitivity in humans: effects in vivo of antibody blockade in obese NIDDM patients and in vitro upon human cultured myotubes

A comparative study on the effects of diet and exercise, metformin and metformin+pioglitazone treatment on NIDDM patients

A comparative study on two groups of newly diagnosed nonobese and obese NIDDM patients who were 15 in each group and treated by diet cum exercise and metfromin monotherapy respectively and a third group of 15 obese NIDDM patients whose hyperglycemia was not first controlled by a combination therapy of metformin and sulfonylurea and therefore changed over to a different combination therapy of metformin and ploglitazone, was carried out before and after a period of three months treatment. The mild hyperglycemia in the 1(st) group and the moderate or severe hyperglycemia with accompanied disorders of serum enzymes such as AST, ALT, GGT and the level of HBA(10) observed with 2(nd) and 3(rd) groups of obese NIDDM patients were significantly ameliorated by the respective mode of treatments. Here the efficacies of the three types of treatment are substantiated and further it specifically depicts the success with the choice of combination therapy with metformin and pioglitazone in the third group of obese diabetics.

Reduced glucose uptake precedes insulin signaling defects in adipocytes from heterozygous GLUT4 knockout mice.

Decreased GLUT4 expression, impaired insulin receptor (IR), IRS-1, and pp60/IRS-3 tyrosine phosphorylation are characteristics of adipocytes from insulin-resistant animal models and obese NIDDM humans. However, the sequence of events leading to the development of insulin signaling defects and the significance of decreased GLUT4 expression in causing adipocyte insulin resistance are unknown. The present study used male heterozygous GLUT4 knockout mice (GLUT4(+/-)) as a novel model of diabetes to study the development of insulin signaling defects in adipocytes with the progression of whole body insulin resistance and diabetes. Male GLUT4(+/-) mice with normal fed glycemia and insulinemia (N/N), normal fed glycemia and hyperinsulinemia (N/H), and fed hyperglycemia with hyperinsulinemia (H/H) exist at all ages. The expression of GLUT4 protein and the maximal insulin-stimulated glucose transport was 50% decreased in adipocytes from all three groups. Insulin signaling was normal in N/N adipose cells. From 35 to 70% reductions in insulin-stimulated tyrosine phosphorylation of IR, IRS-1, and pp60/IRS-3 were noted with no changes in the cellular content of IR, IRS-1, and p85 in N/H adipocytes. Insulin-stimulated protein tyrosine phosphorylation was further decreased to 12-23% in H/H adipose cells accompanied by 42% decreased IR and 80% increased p85 expression. Insulin-stimulated, IRS-1-associated PI3 kinase activity was decreased by 20% in N/H and 68% reduced in H/H GLUT4(+/-) adipocytes. However, total insulin-stimulated PI3 kinase activity was normal in H/H GLUT4(+/-) adipocytes. Taken together, these results strongly suggest that hyperinsulinemia triggers a reduction of IR tyrosine kinase activity that is further exacerbated by the appearance of hyperglycemia. However, the insulin signaling cascade has sufficient plasticity to accommodate significant changes in specific components without further reducing glucose uptake. Furthermore, the data indicate that the cellular content of GLUT4 is the rate-limiting factor in mediating maximal insulin-stimulated glucose uptake in GLUT4(+/-) adipocytes.

Inositol Phosphoglycans in Diabetes and Obesity: Urinary Levels of IPG A-Type and IPG P-Type, and Relationship to Pathophysiological Changes

Measurements have been made, in adult male diabetic patients and control subjects, of the urinary content of inositol phosphoglycans (IPGs), the IPG A-type and IPG P-type forms, which, among other actions, regulate pathways of glucose utilization, lipogenesis, triglyceride formation, and pyruvate dehydrogenase (PDH) activity. Urine samples from the entire diabetic group showed a 2- to 3-fold increase in IPG A-type, and a fall in the IPG P-type:IPG A-type ratio relative to the control group. Subdivision of the diabetic patients into lean IDDM and obese NIDDM groups revealed significant differences in the IPG P-type:IPG A-type ratio between these groups, this ratio decreasing with increases in the body mass index (BMI). Analysis of the relationships among IPGs and HbA1, blood pressure, and BMI indicated that a fall in the IPG P-type:IPG A-type ratio correlated with a rise in the HbA1 (indicative of impaired glycemic control), with increased systolic blood pressure and increased obesity, all factors linked to Syndrome X. There was a parallism between the profile of the IPG P-type:IPG A-type ratio and the well-established pattern of insulin resistance and BMI. In vitro studies of the effects of alterations in the IPG P-type:IPG A-type ratio on the activation of the pyruvate dehydrogenase complex (PDH complex) at the PDH phosphatase reaction demonstrated that IPG A-type forms antagonized the stimulation of the PDH phosphatase by IPG P-type forms, thus having a negative effect on the conversion of PDH to the active, dephosphorylated, form. This observation could provide a mechanism whereby the shifts in the IPG P-type:IPG A-type ratio reported above could change the metabolic pattern from one directed to glucose oxidation to one more directed toward energy conservation and lipid storage.

Increased hepatic glucose production and decreased hepatic glucose uptake at the prediabetic phase in the Otsuka Long-Evans Tokushima Fatty rar model

To investigate the time course of the hepatic glucose metabolism in non—insulin-dependent diabetes (NIDDM), we measured hepatic glucose production (HGP) and first-pass uptake of portal glucose infusion by the liver (HGU) using dual-tracer methods in a NIDDM model, Otsuka Long-Evans Tokushima Fatty (OLETF) rats, and in normal controls, Long-Evans Tokushima Otsuka (LETO) rats, at 8, 14, and 28 weeks of age (n = 5, respectively). The fasting plasma glucose level in OLETF rats was significantly higher than in LETO rats at 28 weeks of age (8.9 ± 1.7 v 6.3 ± 0.4 mmol/L, P < .01), while there was no significant difference at 8 and 14 weeks. Hyperinsulinemia in OLETF rats appeared at ≥8 weeks of age. Basal HGP was significantly higher in OLETF than in LETO rats at 8 and 28 weeks (8 weeks, 12.7 ± 1.7 v 9.4 ± 1.8 mg · kg −1 · min −1, P < .05; 28 weeks, 10.9 ± 1.6 v 7.1 ± 1.3 mg · kg −1 · min −1, P < .01). At 14 weeks, basal HGP was not sinificantly different between OLETF and LETO rats. However, at all study points, HGU during a portal glucose infusion was significantly lower in OLETF than in LETO rats (8 weeks, 0.9 ± 0.2 v 2.3 ± 0.5, P < .01; 14 weeks, 0.8 ± 0.3 v 1.4 ± 0.3, P < .05; 28 weeks, 0.7 ± 0.2 v 1.4 ± 0.3 mg · kg −1 · min −1, P < .01). Fasting plamsa free fatty acid (FFA) levels were not significantly different between OLETF and LETO, except at 8 weeks. Suppression of plasma FFA levels by endogenous insulin during a portal glucose infusion was impaired in OLETF rats compared with LETO rats. In summary, this study demonstrates that derangement of hepatic glucose handling, such as increased basal HGP and decreased HGU, is observed in obese NIDDM model OLETF rats at the prediabetic phase when hyperglycemia is still not apparent. Furthermore, these derangements may be accompanied by impaired lipid metabolism.

Is Insulin the Only Treatment for Obese NIDDM Patients Poorly Controlled By Oral Hypoglycemic Agents?b

Is Insulin the Only Treatment for Obese NIDDM Patients Poorly Controlled By Oral Hypoglycemic Agents?b

Insulin resistance in obese subjects and newly diagnosed NIDDM patients and derangements of pyruvate dehydrogenase in their circulating lymphocytes.

In circulating lymphocytes of individuals with insulin resistance and overt hyperglycaemia (NIDDM patients), alterations, affecting pyruvate dehydrogenase (PDH), the key enzyme in glucose oxidative breakdown, have been observed. They include below normal enzyme activity and, in vitro, no enzyme response to insulin at low physiological levels (5 microU/ml) as well as activation up to the basal values of controls with insulin at high physiological levels (50 microU/ml), instead of activation and inhibition respectively, as in controls. To investigate whether these alterations characterize circulating lymphocytes of individuals with insulin resistance in whom derangements of glucose homeostasis are absent (obese subjects with normal glucose tolerance), or present but still controllable (nonobese and obese newly diagnosed NIDDM patients on an appropriate diet). Thirty obese subjects (BMI 36 +/- 3) responding normally to an oral glucose tolerance (OGT) test; 60 newly diagnosed NIDDM patients (30 nonobese, BMI 22 +/- 4 and 30 obese, BMI 38 +/- 2); 30 nonobese (BMI 21 +/- 5) and nondiabetic subjects, with no family history for NIDDM, served as controls. Evaluation of PDH activity in circulating lymphocytes before and after exposure to insulin at 5 and 50 microU/ml, and of clinical parameters before and during an OGT test. 1) in circulating lymphocytes of obese nondiabetic subjects as well as obese and nonobese newly diagnosed NIDDM patients, PDH activity was significantly below normal. In vitro, enzyme response to insulin at 5 microU/ml was reduced in nonobese NIDDM patients with respect to controls, and absent in obese nondiabetic subjects and obese NIDDM patients. Enzyme response to insulin at 50 microU/ml was reversed in all individuals, which allowed enzyme activity to recover up to the basal level of controls. 2) In NIDDM patients and obese nondiabetic subjects, undergoing an OGT test, the area under the glycaemic curve (g-AUC) was as expected; the area under the insulinaemic curve (i-AUC) was increased in both groups with respect to controls, but significantly only in the latter. In individuals with insulin resistance PDH activity in their circulating lymphocytes rises up to basal levels of controls, only if these cells are exposed to insulin at high physiological concentrations, and g-AUC is normal only in those subjects who have significantly increased i-AUC. This suggests that with insulin at sufficiently high concentrations both parameters can be corrected. We conclude that the derangements responsible for the alterations of the two parameters share common features and thus the described PDH alterations in circulating lymphocytes reflect systemic insulin resistance whether accompanied by hyperglycaemia or not.

1.P.73 Weight reduction improves cholesterol absorption and synthesis in relation to improved glucose metabolism of obese NIDDM patients

1.P.73 Weight reduction improves cholesterol absorption and synthesis in relation to improved glucose metabolism of obese NIDDM patients

Demographic and Clinical Features of Diabetes Mellitus in 1095 Yemeni Patients

The ever-increasing incidence of diabetes mellitus is a cause for growing public health concern in both developed and developing countries. In this study, we aim to explore the special demographic and clinical features of diabetes, as seen in a large sample of Yemeni patients, and to compare these features with those reported in other countries. All patients referred to our diabetic clinic over a five-year period were investigated according to a standardized protocol. Data was collected and fed into a personal computer with a software statistical package for analysis. The relative frequencies of clinical classes of diabetes were 10.5% for IDD, 58.6% for non-obese NIDDM; 26.2% for obese NIDDM, and 4.7% for IGT. In the IDDM class, the age-specific relative frequency rate showed a higher and earlier onset peak frequency in females than in males. Among NIDDM class, about 31% of patients were diagnosed under the age of 45 years, and only 12% were first diagnosed after the age of 65 years. Most NIDDM patients came from social classes I and II (professionals and intermediate professionals) and most IDDM patients came from social class IIIM (skilled manual). A positive family history of diabetes among first-degree relatives of index patients was observed in 33.7% of IDDM patients, in 30% of non-obese NIDDM patients, in 39.2% of obese NIDDM patients and 32% of IGT patients. Female NIDDM patients had a significantly higher mean body mass index (BMI) than males (P<0.0001). Hypertension was recognized in 24.2% of the diabetic population aged 20 to A(3) 65 years. Large vessel disease (LVD) was observed in 28% of patients, small vessel disease (SVD) in 45%, and peripheral neuropathy in 40.7%. Inadequate glycemic control was noticed during follow-up in the majority of patients. Diabetes mellitus in Yemen, especially NIDDM, is characterized by an earlier age at onset, and predominance of males and non-obese NIDM subclass. Other characteristics include moderate genetic susceptibility, inadequate glycemic control and high prevalence of chronic complications.

Intake of a Diet High in Trans Monounsaturated Fatty Acids or Saturated Fatty Acids: Effects on postprandial insulinemia and glycemia in obese patients with NIDDM

High intake of trans fatty acids and saturated fatty acids (SFAs) is known to increase the risk of coronary heart disease. We studied the effects of diets enriched in various fatty acids on postprandial insulinemia and fasting serum levels of lipids and lipoproteins in obese patients with NIDDM. Sixteen obese NIDDM patients were studied in a free-living outpatient regimen. After a run-in period, the patients received three different isocaloric diets for 6 weeks using a randomized crossover design. The patients were instructed to keep the energy intake from carbohydrate and protein constant at 50 and 20 E% (percent of energy intake), respectively, on all three diets. The fat composition of the diets differed: saturated fat (SAT) diet (20 E% SFAs, 5 E% polyunsaturated fatty acids [PUFAs], and 5 E% monounsaturated fatty acids [MUFAs]) versus cis monounsaturated fatty acid (CMUFA) diet (20 E% cis-MUFAs, 5 E% PUFAs, and 5 E% SFAs) versus trans monounsaturated fatty acid (TMUFA) diet (20 E% trans-MUFAs, 5 E% PUFAs, and 5 E% SFAs). Fasting serum levels of lipids and lipoproteins were measured at baseline and in the fasting state before meal tolerance tests at the end of each study period. Insulin secretion was assessed from incremental serum insulin and C-peptide responses during the meal tests. BMI, waist-to-hip ratio, and glycemic control remained stable throughout the study. After meal stimulation, postprandial glycemic responses were similar on all diets; however, serum insulin and C-peptide responses were greater following the TMUFA and SAT diets than following the baseline or CMUFA diets (P < 0.05). No statistical difference was found in fasting levels of serum lipids (total cholesterol, triglyceride, phospholipid, and nonesterified fatty acids) or lipoproteins of HDL cholesterol, VLDL cholesterol, LDL cholesterol, and apolipoprotein B between diets. In the presence of unchanged glycemia, both dietary trans fatty acids and SFAs induce an increase in postprandial insulinemia in obese patients with NIDDM.

Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation.

We examined the effect of physiological hyperinsulinemia on insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation and phosphatidylinositol (PI) 3-kinase activity in skeletal muscle from six lean-to-moderately obese NIDDM patients and six healthy subjects. A rise in serum insulin levels from approximately 60 to approximately 650 pmol/l increased IRS-1 tyrosine phosphorylation sixfold over basal levels in control muscle (P < 0.01), whereas no significant increase was noted in NIDDM muscle. The reduced IRS-1 phosphorylation in the NIDDM muscle was not related to changes in IRS-1 protein content, since IRS-1 protein expression was similar between control and NIDDM subjects (16.0 +/- 1.7 vs. 22.9 +/- 4.0 arbitrary units/mg protein for control and NIDDM, respectively; NS). Physiological hyperinsulinemia increased PI 3-kinase activity in control muscle twofold (P < 0.01), whereas no increase in insulin-stimulated PI 3-kinase activity was noted in the NIDDM muscle. Furthermore, in vitro insulin-stimulated (600 pmol/l) 3-O-methylglucose transport was 40% lower in isolated muscle from NIDDM subjects (P < 0.05). The present findings couple both reduced insulin-stimulated IRS-1 tyrosine phosphorylation and PI 3-kinase activity to the impaired insulin-stimulated glucose transport in skeletal muscle from lean-to-moderately obese NIDDM subjects.

NIDDM in the elderly.

We conducted this study to assess the metabolic alterations in elderly patients with NIDDM. Healthy, lean (n = 15; age, 73 +/- 1 years; BMI, 23.8 +/- 0.5 kg/m2), and obese (n = 10; age, 71 +/- 1 years; BMI, 28.9 +/- 1.2 kg/m2) control subjects and lean (n = 10; age, 75 +/- 2 years; BMI, 24.0 +/- 0.5 kg/m2) and obese (n = 23; age, 73 +/- 1 years; BMI, 29.9 +/- 0.7 kg/m2) NIDDM patients underwent a 3-h glucose tolerance test, a 2-h hyperglycemic glucose clamp study, and a 3-h euglycemic glucose clamp study with tritiated glucose methodology to measure glucose production and disposal rates. Waist-to-hip ratio (WHR) was greater in both lean and obese NIDDM patients than in control subjects. Insulin responses during the oral glucose tolerance test were similar in obese subjects (control subjects: 417 +/- 64 pmol/l; NIDDM patients: 392 +/- 47 pmol/l) but were reduced in lean NIDDM patients (control subjects: 374 +/- 34 pmol/l; NIDDM patients: 217 +/- 20 pmol/l, P < 0.01). Lean and obese NIDDM patients had absent first-phase insulin responses during the hyperglycemic clamp. Second-phase insulin responses were reduced in lean (P < 0.01 vs. control subjects by analysis of variance) but not obese NIDDM patients. Hepatic glucose output was not increased in lean or obese NIDDM patients. Steady-state (150-180 min) glucose disposal rates were 16% less in lean NIDDM patients (control subjects: 8.93 +/- 0.37 mg.kg LBM (lean body mass)-1.min-1; NIDDM patients: 7.50 +/- 0.28 mg.kg LBM-1.min-1, P < 0.05) and 37% less in obese NIDDM patients (control subjects: 8.17 +/- 0.38 mg.kg LBM-1.min-1; NIDDM patients: 5.03 +/- 0.36 mg.kg LBM-1.min-1, P < 0.001). Lean elderly NIDDM patients have a profound impairment in glucose-induced insulin release but mild resistance to insulin-mediated glucose disposal. Obese elderly NIDDM patients have adequate circulating insulin, but marked resistance to insulin-mediated glucose disposal. Hepatic glucose output is not increased in elderly NIDDM patients.

Ultradian Oscillations of Leptin Secretion in Humans

We have recently demonstrated the nocturnal increase in leptin secretion in humans. In the present study we have examined the pulsatile pattern of leptin secretion using two different experimental protocols. The first protocol utilized blood samples withdrawn at 30 minute intervals immediately after meals, at 1 hour intervals between meals, and at 2 hour intervals during the night from 4 lean, 11 obese, and 5 obese NIDDM subjects. Analysis of circulating leptin levels by ULTRA algorithmic program and using matched intra-assay coefficient of variations demonstrated 1 to 7 ultradian oscillations with a mean of 3.25 ± 0.36 (SEM) pulses per 24 hour period (period: 10.0 ± 1.5 hours; mean relative amplitude: 0.52 ± 0.06, n=20). Significant positive correlations were observed for changes in absolute amplitude with body mass index (p<0.025) and fasting leptin levels (<0.0001). In the second series of experiments utilizing 15 minute blood sampling from 10 overnight fasted obese subjects (BMI 35.9 ± 2.0 kg/m2), ultradian oscillations for leptin were more frequent, i.e., 2 to 7 oscillations (4.20 ± 0.59), over a 12 hour duration (period: 3.44 ± 0.49; mean relative amplitude: 0.28 ± 0.03). The number of oscillations over a 12 hour period correlated significantly with BMI (p< 0.001), fasting leptin levels (p< 0.01), and absolute amplitude (p< 0.005) in a 15 minute sampling protocol. In summary, similar to other hormones, ultradian oscillations of leptin are observed in humans, although the physiological significance in relation to obesity or feeding behavior is not yet understood.

Protein metabolism in diabetes mellitus

Insulin deficiency is a protein catabolic state. In vivo studies have shown that insulin enhances short-side-chain amino acid intracellular uptake, stimulates transcription and translation of RNA, increases the gene expression of albumin and other proteins and inhibits liver protein breakdown enzymes. In IDDM patients most of the whole-body protein turnover studies have shown that insulin deficiency increases protein breakdown and increases amino acid oxidation and that these effects are reversed by insulin treatment. Recent studies have demonstrated that a substantial increase in leucine transamination during insulin deprivation contributes to leucine catabolism in IDDM patients. Protein synthesis in the insulin-deprived state is also increased although to a lesser extent than protein breakdown, and this increased whole-body protein synthesis is reduced with an insulin infusion; thus the effects of insulin are largely mediated through its effects on protein breakdown. The metabolic derangements in diabetes frequently involve disturbances in substrates and hormones other than insulin. The observed effects of insulin deficiency in diabetic patients vary in different body compartments; most of the effects of insulin on protein synthesis appear to occur in non-muscular tissues especially in the splanchnic area. In addition, insulin has a differential effect on hepatic protein synthesis, i.e. inhibits fibrinogen synthesis and promotes albumin synthesis. Insulin's anticatabolic effect in IDDM patients is largely due to its inhibition of protein breakdown. The net protein anabolism due to insulin occurs largely in skeletal muscle. In patients with NIDDM these effects are not noted, presumably because of residual endogenous insulin secretion. In fact, treatments that result in improvement of glucose metabolism in obese NIDDM patients do not affect protein metabolism.

Effects of an Engineered Human Anti–TNF-α Antibody (CDP571) on Insulin Sensitivity and Glycemic Control in Patients With NIDDM

Inhibition of tumor necrosis factor (TNF)-alpha action has recently been shown to reverse insulin resistance dramatically and to improve glycemic control in obese rodents. This double-blind study was designed to assess the effects of a recombinant-engineered human TNF-alpha-neutralizing antibody (CDP571) on glucose homeostasis in obese NIDDM patients. Glycemic control and insulin sensitivity were monitored in 21 NIDDM subjects for a 2-week run-in and then for 6 weeks after treatment in a randomized fashion with a single intravenous dose of either CDP571 (5 mg/kg) or an equivalent volume of normal saline. The prolonged half-life of the antibody ensured adequate plasma levels as measured throughout the study. Concentrations of fasting glucose (CDP571: 10.0 +/- 0.8, 10.1 +/- 0.8, 10.0 +/- 1.0; placebo: 8.5 +/- 0.6, 8.1 +/- 0.5, 8.7 +/- 0.8 mmol/l at baseline, day 1, and week 4, respectively), fasting serum insulin (CDP571: 21.2 +/- 2.8, 21.0 +/- 2.8, 24.8 +/- 3.3; placebo: 19.0 +/- 2.8, 20.8 +/- 2.9, 17.5 +/- 2.2 pmol/l, respectively), and C-peptide remained unaffected by the type of treatment throughout the study. The percentage rate of glucose clearance per minute (KITT) during intravenous insulin sensitivity tests was identical in the CDP571 and placebo groups at baseline and also at 1 and 4 weeks after treatment (mean +/- SE; CDP571: 1.33 +/- 0.21, 1.44 +/- 0.25, 1.26 +/- 0.18; placebo: 1.38 +/- 0.15, 1.47 +/- 0.20, 1.52 +/- 0.20; P = 0.85, 0.93, and 0.36, respectively). TNF-alpha neutralization over a period of 4 weeks had no effect on insulin sensitivity in obese NIDDM subjects.

The effect of metformin on liver blood flow in vivo in normal subjects and patients with non insulin dependent diabetes

We previously reported that metformin improves insulin-mediated glucose liver metabolism in patients with non insulin dependent diabetes (NIDDM). It is not clear whether this is a direct effect of metformin on liver metabolism or mediated by other mechanisms such as increased liver blood flow. In this respect it has recently been reported that metformin increases hepatic blood flow (HBF) in diabetic rats. The aim of this study was to evaluate whether the administration of metformin is associated with modifications in HBF in humans. Patients affected by NIDDM ( n = 11) and normal subjects ( n = 6) were studied. In the first protocol HBF was investigated in six overweight (BMI 27 ± 2 Kg/m 2) NIDDM patients and six normal subjects (age and BMI matched) already on metformin treatment before and 2 h after the administration of 500 mg metformin. In the second protocol HBF was investigated in obese (BMI 32 ± 1 Kg/m 2) NIDDM patients ( n = 5) in good metabolic control before and after 15 days of metformin at the dose of 1 g daily. HBF was measured by intravenous injection of 3 mCi 99mTc-phytate. In both protocols no significant changes in HBF were observed following metformin administration either in NIDDM patients or normal subjects. No significant differences were observed in HBF between diabetic patients and normal subjects. These data indicate that metformin has no effect on HBF in man. The previously reported improvement of insulin mediated liver metabolism induced by metformin is likely to be a consequence of the direct effect of the drug at hepatocyte level which is independent of HBF modifications

Quantitative and Qualitative Derangement of Apolipoprotein B-Containing Lipoproteins as a Risk Factor for Diabetic Macroangiopathy in Nonobese NIDDM Subjects

Cholesterol, triglyceride (TG), and apolipoprotein (apo) B were determined in plasma and in lipoprotein subfractions (VLDL, intermediate-density lipoproteins [IDL], LDL, and HDL) in nonobese NIDDM subjects, who were classified into well-controlled, fairly controlled, or poorly controlled states with or without macrovascular complications (macroangiopathy [MA]). The same analyses were also performed on subjects who had coronary artery disease (CAD) with stable angina pectoris (SA) or unstable angina pectoris (UA) and acute myocardial infarction, cerebrovascular disease (CVD) with atherothrombotic or lacunar infarction, and arteriosclerosis obliterans (ASO). In nonobese NIDDM subjects, the number of apoB-containing lipoproteins (VLDL, IDL, and LDL) increased. This alteration was more prominent in subjects with poorly or fairly controlled disease as well as in subjects with MA, but not in those with well-controlled NIDDM. Cholesterol/apoB in LDL decreased in subjects with poorly or fairly controlled diabetes or with MA and was correlated with low HDL cholesterol. The disorder is characterized by hyperbetalipoproteinemia with elevated LDL cholesterol and small dense LDL. In obese NIDDM subjects, the similar disorder was more pronounced. Glycemic control had less effect and hyperinsulinemia, if present, aggravated the lipid disorder. In those with CAD, the number of IDLs increased and the LDL fraction had the properties of small dense LDL. HDL cholesterol decreased. In those with UA, the LDL number increased without elevation of LDL cholesterol, indicating typical hyperbetalipoproteinemia. The subjects with atherothrombotic brain infarction, an increased number of small-sized LDLs was noted. In those with ASO, the number of VLDL and IDL increased with small LDL. HDL cholesterol decreased in those with CAD, cerebrovascular disease, and ASO. Since similar quantitative and qualitative alterations of apoB-containing lipoprotein have been observed in NIDDM patients as well as in those with macrovascular diseases, diabetic patients are thought to be more susceptible to the initiation and progression of atheromatous lesions in coronary, brain, and peripheral arteries.

Potentiation of effects of weight loss by monounsaturated fatty acids in obese NIDDM patients

Potentiation of effects of weight loss by monounsaturated fatty acids in obese NIDDM patients