Effect of dietary Platycodon grandiflorum on the improvement of insulin resistance in obese Zucker rats

The effect of dietary Platycodon grandiflorum on the improvement of insulin resistance and lipid profile was investigated in lean (Fa/-) and obese (fa/fa) Zucker rats, a model for noninsulin dependent diabetes mellitus. Dietary Platycodon grandiflorum feeding for 4 weeks resulted in a significant decrease in the concentration of plasma triglyceride in both lean and obese Zucker rats. Furthermore, dietary Platycodon grandiflorum markedly decreased both plasma cholesterol and fasting plasma insulin levels, and significantly decreased the postprandial glucose level at 30 min during oral glucose tolerance test in obese Zucker rats. Although there was no statistical significance, the crude glucose transporter 4 protein level of obese rats fed Platycodon grandiflorum tended to increase when compared with that of obese control rats. Therefore, the present results suggested that dietary Platycodon grandiflorum may be useful in prevention and improvement of metabolic disorders characterized by hyperinsulinemia states such as noninsulin dependent diabetes mellitus, syndrome X, and coronary artery disease.     

Hepatic Insulin Resistance in Obese Non-Diabetic Subjects and in Type 2 Diabetic Patients

Objective: Obese non-diabetic patients are characterized by an extra-hepatic insulin resistance. Whether obese patients also have decreased hepatic insulin sensitivity remains controversial. Research Methods and Procedures: To estimate their hepatic insulin sensitivity, we measured the rate of exogenous insulin infusion required to maintain mildly elevated glycemia in obese patients with type 2 diabetes, obese non-diabetic patients, and lean control subjects during constant infusions of somatostatin and physiological low-glucagon replacement infusions. To account for differences in insulin concentrations among the three groups of subjects, an additional protocol was also performed in healthy lean subjects with higher insulin infusion rates and exogenous dextrose infusion. Results: The insulin infusion rate required to maintain glycemia at 8.5 mM was increased 4-fold in obese patients with type 2 diabetes and 1.5-fold in obese non-diabetic patients. The net endogenous glucose production (measured with 6,6-²H₂-glucose) and total glucose output (measured with 2-²H₁-glucose) were ∼30% lower in the patients than in the lean subjects. Net endogenous glucose production and total glucose output were both markedly increased in both groups of obese patients compared with lean control subjects during hyperinsulinemia. Discussion: Our data indicate that both obese non-diabetic and obese type 2 diabetic patients have a blunted suppressive action of insulin on glucose production, indicating hepatic and renal insulin resistance.     

The insulin-mediated modulation of visually evoked magnetic fields is reduced in obese subjects

Background

Insulin is an anorexigenic hormone that contributes to the termination of food intake in the postprandial state. An alteration in insulin action in the brain, named “cerebral insulin resistance”, is responsible for overeating and the development of obesity.

Methodology/Principal Findings

To analyze the direct effect of insulin on food-related neuronal activity we tested 10 lean and 10 obese subjects. We conducted a magnetencephalography study during a visual working memory task in both the basal state and after applying insulin or placebo spray intranasally to bypass the blood brain barrier. Food and non-food pictures were presented and subjects had to determine whether or not two consecutive pictures belonged to the same category.Intranasal insulin displayed no effect on blood glucose, insulin or C-peptide concentrations in the periphery; however, it led to an increase in the components of evoked fields related to identification and categorization of pictures (at around 170 ms post stimuli in the visual ventral stream) in lean subjects when food pictures were presented. In contrast, insulin did not modulate food-related brain activity in obese subjects.

Conclusions/Significance

We demonstrated that intranasal insulin increases the cerebral processing of food pictures in lean whereas this was absent in obese subjects. This study further substantiates the presence of a “cerebral insulin resistance” in obese subjects and might be relevant in the pathogenesis of obesity.     

Inhibition of insulin, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) secretion by octreotide has no effect on post-heparin plasma lipoprotein lipase activity.

This study examines the immediate effect of modulating postprandial insulin and insulinotropic hormone (glucose-dependent insulinotropic polypeptide, GIP; glucagon-like peptide-1, GLP-1) secretion on the activation of lipoprotein lipase (LPL) in six lean and six obese age-matched women. Subjects were given, on two separate occasions, 340 kcal of carbohydrate alone or combined with an IV infusion of octreotide, (100 microg infusion from 30 min before the meal for 150 min). Post-heparin LPL activity (10,000 U) was measured on each occasion 120 minutes post-carbohydrate. Following oral carbohydrate postprandial plasma insulin levels were significantly higher in obese subjects than in lean (p < 0.01). Glucose tolerance was slightly impaired in obese subjects. Insulin, GIP and GLP-1 secretion post-carbohydrate was markedly reduced by octreotide in lean and obese subjects. LPL activity was similar in the two groups after carbohydrate administration and was unaffected by octreotide. Inhibition of postprandial insulin, GIP and GLP-1 secretion acutely did not reduce post-heparin LPL activity either in lean or obese subjects.     

Reduced insulin-mediated citrate synthase activity in cultured skeletal muscle cells from patients with type 2 diabetes: evidence for an intrinsic oxidative enzyme defect

In myotubes established from patients with type 2 diabetes (T2D), lipid oxidation and insulin-mediated glucose oxidation are reduced, whereas in myotubes from obese non-diabetic subjects, exposure to palmitate impairs insulin-mediated glucose oxidation. To determine the underlying mechanisms of these metabolic malfunctions, we studied mitochondrial respiration, uncoupled respiration and oxidative enzyme activities (citrate synthase (CS), 3-hydroxy-acyl-CoA-dehydrogenase activity (HAD)) before and after acute exposure to insulin and/or palmitate in myotubes established from healthy lean and obese subjects and T2D patients. Basal CS activity was lower (14%) in diabetic myotubes compared with myotubes from lean controls (P=0.03). Incubation with insulin (1 microM) for 4 h increased the CS activity (26-33%) in myotubes from both lean (P=0.02) and obese controls (P<0.001), but not from diabetic subjects. Co-incubation with palmitate (0.6 mM) for 4 h abolished the stimulatory effect of insulin on CS activity in non-diabetic myotubes. No differences were detected in mitochondrial respiration and HAD activity between myotubes from non-diabetic subjects and T2D patients, and none of these measures responded to high levels of insulin and/or palmitate. These results provide evidence for an intrinsic defect in CS activity, which may play a role in the pathogenesis of T2D. Moreover, the data suggest that insulin resistance at the CS level can be induced by exposure to high free fatty acid levels.     

Increased collagen content in insulin-resistant skeletal muscle

Oversupply and underutilization of lipid fuels are widely recognized to be strongly associated with insulin resistance in skeletal muscle. Recent attention has focused on the mechanisms underlying this effect, and defects in mitochondrial function have emerged as a potential player in this scheme. Because evidence indicates that lipid oversupply can produce abnormalities in extracellular matrix composition and matrix changes can affect the function of mitochondria, the present study was undertaken to determine whether muscle from insulin-resistant, nondiabetic obese subjects and patients with type 2 diabetes mellitus had increased collagen content. Compared with lean control subjects, obese and type 2 diabetic subjects had reduced muscle glucose uptake (P<0.01) and decreased insulin stimulation of tyrosine phosphorylation of insulin receptor substrate-1 and its ability to associate with phosphatidylinositol 3-kinase (P<0.01 and P<.05). Because it was assayed by total hydroxyproline content, collagen abundance was increased in muscle from not only type 2 diabetic patients but also nondiabetic obese subjects (0.26+/-0.05, 0.57+/-0.18, and 0.67+/- 0.20 microg/mg muscle wet wt, lean controls, obese nondiabetics, and type 2 diabetics, respectively), indicating that hyperglycemia itself could not be responsible for this effect. Immunofluorescence staining of muscle biopsies indicated that there was increased abundance of types I and III collagen. We conclude that changes in the composition of the extracellular matrix are a general characteristic of insulin-resistant muscle.     

In vivo activation of ROCK1 by insulin is impaired in skeletal muscle of humans with type 2 diabetes

To determine whether serine/threonine ROCK1 is activated by insulin in vivo in humans and whether impaired activation of ROCK1 could play a role in the pathogenesis of insulin resistance, we measured the activity of ROCK1 and the protein content of the Rho family in vastus lateralis muscle of lean, obese nondiabetic, and obese type 2 diabetic subjects. Biopsies were taken after an overnight fast and after a 3-h hyperinsulinemic euglycemic clamp. Insulin-stimulated GDR was reduced 38% in obese nondiabetic subjects compared with lean, 62% in obese diabetic subjects compared with lean, and 39% in obese diabetic compared with obese nondiabetic subjects (all comparisons P < 0.001). Insulin-stimulated IRS-1 tyrosine phosphorylation is impaired 41-48% in diabetic subjects compared with lean or obese subjects. Basal activity of ROCK1 was similar in all groups. Insulin increased ROCK1 activity 2.1-fold in lean and 1.7-fold in obese nondiabetic subjects in muscle. However, ROCK1 activity did not increase in response to insulin in muscle of obese type 2 diabetic subjects without change in ROCK1 protein levels. Importantly, insulin-stimulated ROCK1 activity was positively correlated with insulin-mediated GDR in lean subjects (P < 0.01) but not in obese or type 2 diabetic subjects. Moreover, RhoE GTPase that inhibits the catalytic activity of ROCK1 by binding to the kinase domain of the enzyme is notably increased in obese type 2 diabetic subjects, accounting for defective ROCK1 activity. Thus, these data suggest that ROCK1 may play an important role in the pathogenesis of resistance to insulin action on glucose disposal in muscle of obese type 2 diabetic subjects.     

Similar incretin secretion in obese and non-obese Japanese subjects with type 2 diabetes

Incretin secretion and effect on insulin secretion are not fully understood in patients with type 2 diabetes. We investigated incretin and insulin secretion after meal intake in obese and non-obese Japanese patients with type 2 diabetes compared to non-diabetic subjects. Nine patients with type 2 diabetes and 5 non-diabetic subjects were recruited for this study. Five diabetic patients were obese (BMI ? 25) and 4 patients were non-obese (BMI < 25). In response to a mixed meal test, the levels of immunoreactive insulin during 15-90 min and C-peptide during 0-180 min in non-obese patients were significantly lower than those in obese patients. Total GLP-1 and active GIP levels showed no significant difference between obese and non-obese patients throughout the meal tolerance test. In addition, there were no significant differences between diabetic patients and non-diabetic subjects. In conclusion, incretin secretion does not differ between Japanese obese and non-obese patients with type 2 diabetes and non-diabetic subjects.     

Metabolic abnormalities in first-degree relatives of type 2 diabetics

Diabetic relatives and obese subjects are at increased risk for development of diabetes mellitus, and therefore are classed as potential abnormality of glucose tolerance (POT-AGT). Disturbances of lipid and purine metabolisms have been reported in diabetic and obese non-diabetic subjects. In obese subjects above alterations are probably due to hyperinsulinemia. This study aimed at verifying whether similar metabolic abnormalities could be found in relatives of non-insulin dependent diabetic patients and whether they could be related to possible glucose intolerance. We have studied 10706 outpatients and 95 hospitalized subjects, aged between 20 and 50 years. We have selected 4 groups according to diabetic relationship and body mass index: A (normal weight subjects), B (obese subjects), C (normal weight NIDDM-relatives), D (overweight NIDDM-relatives). The NIDDM-relatives showed higher prevalence of hyperglycemia, as expected; furthermore the relatives with normal glucose tolerance had higher glucose area during OGTT. Serum levels of uric acid and insulin response to oral glucose were increased in all obese subjects, but abnormalities of lipid metabolism and fasting hyperinsulinemia were found only in obese NIDDM-relatives. These results suggest that family history of diabetes mellitus can be a risk for metabolic disturbance even in absence of glucose intolerance. Furthermore some metabolic disorders observed in obese subjects could be due to an associated and not sufficiently investigated family history of diabetes.     

The Male Obese Wistar Diabetic Fatty Rat Is a New Model of Extreme Insulin Resistance

The male obese Wistar Diabetic Fatty (WDF) rat is a genetic model of obesity and non-insulin dependent diabetes (NIDDM). The obese Zucker rat shares the same gene for obesity on a different genetic background but is not diabetic. This study evaluated the degree of insulin resistance in both obese strains by examining the binding and post binding effects of muscle insulin receptors in obese, rats exhibiting hyperinsulinemia and/or hyperglycemia. Insulin receptor binding and affinity and tyrosine kinase activity were measured in skeletal muscle from male WDF fa/fa (obese) and Fa/? (lean) and Zucker fa/fa (obese) and Fa/Fa (homozygous lean) rats. Rats were fed a high sucrose (68% of total Kcal) or Purina stock diet for 14 weeks. At 27 weeks of age, adipose depots were removed for adipose cellularity analysis and the biceps femoris muscle was removed for measurement of insulin binding and insulin-stimulated receptor kinase activity. Plasma glucose (13.9 vs. 8.4 mM) and insulin levels (14,754 vs. 7440 pmoI/L) were significantly higher in WDF obese than in Zucker obese rats. Insulin receptor number and affinity and TK activity were unaffected by diet. Insulin receptor number was significantly reduced in obese WDF rats (2.778 ± 0.617 pmol/mg protein), compared to obese Zucker rats (4.441 ± 0.913 pmol/mg potein). Both obese strains exhibited down regulation of the insulin receptor compared to their lean controls. Maximal tyrosine kinase (TK) activity was significantly reduced in obese WDF rats (505 ± 82 fmol/min/mg protein) compared to obese Zucker rats (1907 ± 610 fmol/min/mg protein). Only obese WDF rats displayed a decrease in TK activity per receptor. These observations establish the obese WDF rat as an excellent model for exploring mechanisms of extreme insulin resistance, particularly post-receptor tyrosine kinase-associated defects, in non-insulin dependent diabetes.     

Postprandial adiponectin levels are unlikely to contribute to the pathogenesis of obesity in Prader-Willi syndrome

AIM: To investigate fasting and postprandial adiponectin levels in PWS patients as compared to obese and lean subjects and whether they could contribute to the pathogenesis of obesity in this syndrome. METHODS: We studied 7 patients with PWS, 16 obese patients and 42 lean subjects for the fasting study. From this group, we evaluated 7 patients with PWS, 7 age-sex-BMI-matched obese non-PWS patients and 7 age-sex-matched lean subjects before and after the administration of 3,139.5 kJ (750 kcal) of a standard liquid meal (53.2% carbohydrate, 30% fat, 16.7% protein) after an overnight fast. Blood samples were obtained every 15 min for the first hour and every 30 min thereafter until 6 h. Adiponectin, IGF-I, glucose, triglycerides, cholesterol, and insulin were measured. RESULTS: Fasting plasma adiponectin levels were lower in PWS than in lean subjects (5.24+/-2.56 vs. 8.28+/-4.63 microg/ml, p=0.041) but higher than in obese patients (4.01+/-1.27 microg/ml, p=0.047). After the meal, adiponectin concentrations mildly decreased in PWS at time point 240 min, while in obese and lean subjects no changes were observed. However, 6-hour postprandial AUC for adiponectin was similar in all three groups. CONCLUSION: Fasting adiponectin levels are low in PWS, but they are so mildly modulated postprandially that these changes do not seem significant for the pathogenesis of obesity in this syndrome.     

Guanine nucleotide binding regulatory proteins in liver from obese humans with and without type II diabetes: Evidence for altered “cross-talk” between the insulin receptor and Gi-proteins

A novel pathway for physiological “cross-talk” between the insulin receptor and the regulatory G_i-protein has been demonstrated. We tested the hypothesis that a coupling defect between G_i and the insulin receptor is present in the liver of obese patients with and without type li diabetes. Insulin 1 × 10^?9 M (～ ED₅₀) and 1 × 10^?7 M (Max) inhibited pertussis toxin-catalyzed ADP ribosylation of G_i in human liver plasma membranes from lean and obese nondiabetic patients. However, 1 × 10^?7 M insulin was without effect in membranes from patients with type II diabetes. This coupling defect was not intrinsic to G_i, since Mg²⁺ and GTPγS inhibited pertussis toxin-catalyzed ADP ribosylation in both diabetic and nondiabetic patients. Binding of insulin of the α-subunit and activation of the tyrosine kinase intrinsic to the β-subunit of the insulin receptor are not responsible for the coupling defect. ¹²⁵I insulin binding is the same in obese patients with or without diabetes. Tyrosine kinase of the insulin receptor is decreased in diabetes. However, a monoclonal antibody to the insulin receptor (MA-20) at equimolar concentrations with insulin equally inhibits pertussis toxin-catalyzed ADP ribosylation of G_i without activating tyrosine kinase or insulin receptor autophosphorylation. Immunodetection of G-proteins suggested that G_i3α was normal in diabetes and G_i1-2α was decreased by 40% in the diabetic group as compared to the obese nondiabetic group but was normal when compared to the lean non diabetic group. We conclude that the novel pathway of insulin signaling involving the regulatory G_i proteins via biochemical mechanisms not directly involving the tyrosine kinase of the insulin receptor is altered in obese type II diabetes and offers a new target for the search of the mechanism(s) of insulin resistance.     

Increased sensitivity to somatostatin in obese Zucker rats

The release of somatostatin from the pancreas and stomach following the ingestion of a meal and its increase in the peripheral circulation elicits an attenuation of postprandial hormone secretion such as insulin, pancreatic polypeptide and gastrin and retards the rate at which nutrients enter the circulation. Reduced tissue somatostatin content and/or an attenuated somatostatin release is associated with hyperinsulinism and obesity in certain animal models. In the obese Zucker rat, however, tissue somatostatin levels are increased and therefore the present study was designed to determine the effect of synthetic somatostatin on basal and postprandial arterial insulin levels in obese and lean Zucker rats. Synthetic somatostatin was infused at doses of 0.25, 0.5, 1 and 5 ng/kg X min before and after the intragastric instillation of a liver extract/sucrose test meal. In the obese rats somatostatin at a dose of 5 ng/kg X min reduced basal plasma insulin levels significantly, whereas no effect of somatostatin was observed on basal insulin levels in the lean animals at all doses employed. The integrated postprandial insulin response was reduced during 0.25, 0.5, 1 and 5 ng/kg X min somatostatin in the obese animals, whereas only 0.5 ng/kg X min and higher doses had an inhibitory effect in the lean rats. The degree of inhibition in relation to the postprandial insulin response during saline infusions was 35-230% in the obese and 30-100% in the lean Zucker rats within the range of somatostatin infusions employed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationship between plasma leptin and zinc levels and the effect of insulin and oxidative stress on leptin levels in obese diabetic patients

Leptin is thought to be a lipostatic signal that contributes to body weight regulation. Zinc plays an important role in appetite regulation also. Our aim is to evaluate the relationship between leptin and zinc in obese and nonobese type 2 diabetic patients and its relationship with oxidative stress and insulin. We studied 25 nonobese nondiabetic women (controls); 35 nonobese diabetic women; and 45 obese diabetic women. Plasma leptin concentration was determined by immunoradiometric assay. Thiobarbituric acid reactive substances (TBARS), markers of oxidative stress, were assayed by the spectrofotometric method. Plasma levels of zinc and insulin were measured by atomic absorption spectrophotometer and electrochemiluminescence methods, respectively. We found that nonobese diabetic patients had significantly lower zinc and higher TBARS levels than control subjects (P<0.01). There was no difference in plasma leptin levels between nonobese diabetic subjects and controls. Obese diabetic subjects had significantly higher plasma leptin, TBARS, and insulin levels and significantly lower plasma zinc levels than nonobese diabetic subjects (for each comparison; P<0.01). The univariate and multivariate analyses demonstrated a significant positive correlation between leptin and body mass index (P<0.01) and insulin (P<0.01), and a significant negative correlation between leptin and zinc in obese subjects. Additionally, TBARS levels was positive correlated with insulin and negative correlated with zinc in obese diabetic subjects. We conclude that zinc may be a mediator of the effects of leptin, although the detailed mechanism is still unknown and requires further investigation. Free radical induced mechanism(s) may be involved in this process.     

Prolactin response to TRH in insulin-dependent diabetes mellitus

17 obese women were examined, 8 of which were diabetic and 9 affected only by essential obesity. These patients, all of whom had become obese during adult life and 8 control subjects were tested for IRI, GH and PRL levels in basal conditions and after infusion of TRH. In the obese and diabetic women fasting GH values were normal while IRI levels were higher than those of the control subjects. In all cases neither IRI nor GH variations during TRH stimulation test. There was no difference in the plasma levels of PRL between the 3 groups when examined in basal conditions. After TRH the hormone increased considerably in all the subjects. In the obese and diabetic obese women the incremental area did not present different values from those observed in the control subjects. In conclusion in insulin-independent diabetes, as in essential obesity, the pharmacological stimulus did not show any evident alteration of the specific hypofisary receptorial system that regulates the secretion of PRL and GH.     

Fatty acid transport protein-1 mRNA expression in skeletal muscle and in adipose tissue in humans

Fatty acid transporter protein (FATP)-1 mRNA expression was investigated in skeletal muscle and in subcutaneous abdominal adipose tissue of 17 healthy lean, 13 nondiabetic obese, and 16 obese type 2 diabetic subjects. In muscle, FATP-1 mRNA levels were higher in lean women than in lean men (2.2 +/- 0.1 vs. 0.6 +/- 0.2 amol/microg total RNA, P < 0.01). FATP-1 mRNA expression was decreased in skeletal muscle in obese women both in nondiabetic and in type 2 diabetic patients (P < 0.02 vs. lean women in both groups), and in all women there was a negative correlation with basal FATP-1 mRNA level and body mass index (r = -0.74, P < 0.02). In men, FATP-1 mRNA was expressed at similar levels in the three groups both in skeletal muscle (0.6 +/- 0.2, 0.6 +/- 0.2, and 0.8 +/- 0.2 amol/microg total RNA in lean, obese, and type 2 diabetic male subjects) and in adipose tissue (0.9 +/- 0.2 amol/microg total RNA in the 3 groups). Insulin infusion (3 h) reduced FATP-1 mRNA levels in muscle in lean women but not in lean men. Insulin did not affect FATP-1 mRNA expression in skeletal muscle in obese nondiabetic or in type 2 diabetic subjects nor in subcutaneous adipose tissue in any of the three groups. These data show a gender-related difference in the expression of the fatty acid transporter FATP-1 in skeletal muscle of lean individuals and suggest that changes in FATP-1 expression may not contribute to a large extent to the alterations in fatty acid uptake in obesity and/or type 2 diabetes.     

Effect of macronutrients, age, and obesity on 6- and 24-h postprandial glucose metabolism in cats

Obesity and age are risk factors for feline diabetes. This study aimed to test the hypothesis that age, long-term obesity, and dietary composition would lead to peripheral and hepatorenal insulin resistance, indicated by higher endogenous glucose production (EGP) in the fasted and postprandial state, higher blood glucose and insulin, and higher leptin, free thyroxine, and lower adiponectin concentrations. Using triple tracer-(2)H(2)O, [U-(13)C(3)] propionate, and [3,4-(13)C(2)] glucose infusion, and indirect calorimetry-we investigated carbohydrate and fat metabolic pathways in overnight-fasted neutered cats (13 young lean, 12 old lean, and 12 old obese), each fed three different diets (high protein with and without polyunsaturated fatty acids, and high carbohydrate) in a crossover design. EGP was lowest in fasted and postprandial obese cats despite peripheral insulin resistance, indicated by hyperinsulinemia. Gluconeogenesis was the most important pathway for EGP in all groups, but glycogen contributed significantly. Insulin and leptin concentrations were higher in old than in young lean cats; adiponectin was lowest in obese cats but surprisingly highest in lean old cats. Diet had little effect on metabolic parameters. We conclude that hepatorenal insulin resistance does not develop in the fasted or postprandial state, even in long-term obese cats, allowing the maintenance of euglycemia through lowering EGP. Glycogen plays a major role in EGP, especially in lean fasted cats, and in the postprandial state. Aging may predispose to insulin resistance, which is a risk factor for diabetes in cats. Mechanisms underlying the high adiponectin of healthy old lean cats need to be further explored.     

Oral salmon calcitonin improves fasting and postprandial glycemic control in lean healthy rats

A novel oral form of salmon calcitonin (sCT) was recently demonstrated to improve both fasting and postprandial glycemic control and induce weight loss in diet-induced obese and insulin-resistant rats. To further explore the glucoregulatory efficacy of oral sCT, irrespective of obesity and metabolic dysfunction, the present study investigated the effect of chronic oral sCT treatment on fasting and postprandial glycemic control in male lean healthy rats. 20 male rats were divided equally into a control group receiving oral vehicle or an oral sCT (2?mg/kg) group. All rats were treated twice daily for 5 weeks. Body weight and food intake were monitored during the study period and fasting blood glucose, plasma insulin and insulin sensitivity were determined and an oral glucose tolerance test (OGTT) performed at study end. Compared with the vehicle group, rats receiving oral sCT had improved fasting glucose homeostasis and insulin resistance, as measured by homeostatic model assessment of insulin resistance index (HOMA-IR), with no change in body weight or fasting plasma insulin. In addition, the rats receiving oral sCT had markedly reduced glycemia and insulinemia during OGTT. This is the first report showing that chronic oral sCT treatment exerts a glucoregulatory action in lean healthy rats, irrespective of influencing body weight. Importantly, oral sCT seems to exert a dual treatment effect by improving fasting and postprandial glycemic control and insulin sensitivity. This and previous studies suggest oral sCT is a promising agent for the treatment of obesity-related insulin resistance and type 2 diabetes.     

Endogenous opiate modulators of insulin secretion in the obese

The effects of endogenous opiates on insulin response to oral glucose load were studied in obese subjects and in lean healthy volunteers. None of these having a family diabetes. After 3 days on an 1,800 cal./m2, 40% carbohydrate diet all subjects underwent two standard 75 g oral glucose tolerance tests (OGTT), one of which was accompanied by an i. v. administration of 10 mg of, an antagonist of opiates, the naloxone. In one group of obese impaired oral glucose tolerance test occurred. All obese, but not the lean healthy volunteers, showed: 1) increased basal plasma insulin levels, 2) higher insulin response to OGTT, 3) a decrease in insulin response to OGTT after naloxone administration, with significant differences at 60 min (p less than 0.01) and 90 min (p less than 0.025). In none of the subjects significant differences were observed in blood glucose levels after OGTT plus naloxone administration. These data suggest that increased endogenous opiates may affect insulin response to glucose in obese with impaired or normal oral glucose tolerance test. At present there seems to be no satisfactory explanation for unchanged blood glucose levels during OGTT with and without naloxone despite a decrease in insulin secretion in the obese patients.     

United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet,sulphonylurea, insulin,or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years.

OBJECTIVE--To assess the relative efficacy of treatments for non-insulin dependent diabetes over three years from diagnosis. DESIGN--Multicentre, randomised, controlled trial allocating patients to treatment with diet alone or additional chlorpropamide, glibenclamide, insulin, or metformin (if obese) to achieve fasting plasma glucose concentrations < or = 6 mmol/l. SETTING--Outpatient diabetic clinics in 15 British hospitals. SUBJECTS--2520 subjects who, after a three month dietary run in period, had fasting plasma glucose concentrations of 6.1-14.9 mmol/l but no hyperglycaemic symptoms. MAIN OUTCOME MEASURES--Fasting plasma glucose, glycated haemoglobin, and fasting plasma insulin concentrations; body weight; compliance; and hypoglycaemia. RESULTS--Median fasting plasma glucose concentrations were significantly lower at three years in patients allocated to chlorpropamide, glibenclamide, or insulin rather than diet alone (7.0, 7.6, 7.4, and 9.0 mmol/l respectively; P < 0.001) with lower mean glycated haemoglobin values (6.8%, 6.9%, 7.0%, and 7.6%, respectively; P < 0.001). Mean body weight increased significantly with chlorpropamide, glibenclamide, and insulin but not diet (by 3.5, 4.8, 4.8, and 1.7 kg; P < 0.001). A similar pattern was seen for mean fasting plasma insulin concentration (by 0.9, 1.2, 2.4, and -0.1 mU/l; P < 0.001). In obese subjects metformin was as effective as the other drugs with no change in mean body weight and significant reduction in mean fasting plasma insulin concentration (-2.5 mU/l; P < 0.001). More hypoglycaemic episodes occurred with sulphonylurea or insulin than with diet or metformin. CONCLUSION--The drugs had similar glucose lowering efficacy, although most patients remained hyperglycaemic. Long term follow up is required to determine the risk-benefit ratio of the glycaemic improvement, side effects, changes in body weight, and plasma insulin concentration.