1,721,019 research outputs found
Phasic insulin release and metabolic regulation in type 2 diabetes
No full textType 2 diabetes is a heterogeneous disorder due to prevalent insulin resistance associated with deficient insulin secretion or to a prevalent defect of insulin secretion associated with impaired insulin action. The definition is supported by the high frequency at which insulin resistance can be demonstrated in type 2 diabetic patients. Nonetheless, insulin resistance is not a sufficient mechanism to cause diabetes. Impaired beta-cell function is a necessary defect in all conditions of impaired glucose regulation; however, it manifests itself in a different manner in fasting and glucose-stimulated conditions. In the fasting state, the basal insulin secretory rate increases as a function of the progressive decline in insulin action. As such, the fasting plasma insulin concentration is often taken as a marker for insulin sensitivity. After glucose challenge, a specific alteration of acute insulin release is an early and progressive defect. The latter might represent an intrinsic defect, but its continuous decline is affected by glucotoxicity and lipotoxicity. To understand the impact of beta-cell dysfunction in type 2 diabetes on metabolic homeostasis, it is useful to consider the different phases of insulin secretion separately. Insulin secretion can be divided into basal (postabsorptive) and stimulated (postprandial) states. The former prevails during the interprandial phases and plays a major role during the overnight fast; the latter regulates glucose metabolism when carbohydrate is abundant and must be disposed of. Data in animals and humans support a crucial physiological role of first-phase insulin secretion in post; prandial glucose homeostasis. This effect is primarily achieved in the liver, allowing prompt inhibition of endogenous glucose production and limiting the post; prandial rise in plasma glucose level. In type 2 diabetes, loss of the early surge of insulin release is an early and quite common defect that may have a pathogenetic role in the development of postprandial hyperglycemia, possibly requiring specific therapeutic intervention
PATHOGENESIS OF NIDDM - A BALANCED OVERVIEW
No full textNon-insulin-dependent diabetes mellitus (NIDDM) results from an imbalance between
insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional
studies have demonstrated that the earliest detectable abnormality in NIDDM is an
impairment in the body's ability to respond to insulin. Because the pancreas is
able to appropriately augment its secretion of insulin to offset the insulin
resistance, glucose tolerance remains normal. With time, however, the beta-cell
fails to maintain its high rate of insulin secretion and the relative
insulinopenia (i.e., relative to the degree of insulin resistance) leads to the
development of impaired glucose tolerance and eventually overt diabetes mellitus.
The cause of pancreatic "exhaustion" remains unknown but may be related to the
effect of glucose toxicity in a genetically predisposed beta-cell. Information
concerning the loss of first-phase insulin secretion, altered pulsatility of
insulin release, and enhanced proinsulin-insulin secretory ratio is discussed as
it pertains to altered beta-cell function in NIDDM. Insulin resistance in NIDDM
involves both hepatic and peripheral, muscle, tissues. In the postabsorptive
state hepatic glucose output is normal or increased, despite the presence of
fasting hyperinsulinemia, whereas the efficiency of tissue glucose uptake is
reduced. In response to both endogenously secreted or exogenously administered
insulin, hepatic glucose production fails to suppress normally and muscle glucose
uptake is diminished. The accelerated rate of hepatic glucose output is due
entirely to augmented gluconeogenesis. In muscle many cellular defects in insulin
action have been described including impaired insulin-receptor tyrosine kinase
activity, diminished glucose transport, and reduced glycogen synthase and
pyruvate dehydrogenase. The abnormalities account for disturbances in the two
major intracellular pathways of glucose disposal, glycogen synthesis, and glucose
oxidation. In the earliest stages of NIDDM, the major defect involves the
inability of insulin to promote glucose uptake and storage as glycogen. Other
potential mechanisms that have been put forward to explain the insulin
resistance, include increased lipid oxidation, altered skeletal muscle capillary
density/fiber type/blood flow, impaired insulin transport across the vascular
endothelium, increased amylin, calcitonin gene-related peptide levels, and
glucose toxicity
The metabolic syndrome is a risk indicator of microvascular and macrovascular complications in diabetes: results from Metascreen, a multicenter diabetes clinic-based survey
No full textOBJECTIVE: We aimed at assessing the degree of association and the predictive power of the metabolic syndrome with regard to clinically detectable complications in patients with diabetes.
RESEARCH DESIGN AND METHODS: Metascreen is a cross-sectional survey of metabolic syndrome and clinically detected diabetes complications performed in 8,497 patients (7,859 with type 2 diabetes and 638 with type 1 diabetes) randomly chosen in 176 diabetes outpatient clinics throughout Italy. The metabolic syndrome was defined according to either the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) or the International Diabetes Federation (IDF) diagnostic criteria. Multivariate analyses of the association(s) between either AHA/NHLBI or IDF metabolic syndrome and clinical complications were performed. Receiver-operator characteristic (ROC) curves were constructed to compare the predictive power of the two sets of diagnostic criteria of the metabolic syndrome.
RESULTS: Either definition of the metabolic syndrome was an independent statistical indicator of the presence of nephropathy and neuropathy (P < 0.02-0.01) in type 1 diabetes and of all complications (P < 0.0001), including cardiovascular disease and retinopathy, in type 2 diabetes. For each complication, the ROC curves based on either AHA/NHLBI or IDF metabolic syndrome were similar to each other and to the ROC curves constructed with all continuous traits compounding the metabolic syndrome.
CONCLUSIONS: The metabolic syndrome, defined according to AHA/NHLBI or IDF diagnostic criteria, is an independent clinical indicator and may be involved in the pathogenesis of both macro- and microvascular complications of diabetes
THE ROLE OF FREE FATTY-ACID METABOLISM IN THE PATHOGENESIS OF INSULIN RESISTANCE IN OBESITY AND NONINSULIN-DEPENDENT DIABETES-MELLITUS
No full textTo investigate the mechanisms of insulin resistance in obesity and
noninsulin-dependent diabetes mellitus (NIDDM), we examined oxidative and
nonoxidative pathways of free fatty acid (FFA) and glucose metabolism in 14 lean
and 17 obese (with normal oral glucose tolerance) nondiabetic subjects and in 8
lean and 8 obese subjects with NIDDM. FFA and glucose metabolism were measured
using the sequential insulin clamp technique in combination with indirect
calorimetry and infusion of [3-3H]glucose and [1-14C]palmitate. Obesity was
characterized by enlarged fat mass, which correlated positively with the plasma
FFA concentration (r = 0.62; P less than 0.01). FFA metabolism was less sensitive
to insulin in obese than in lean nondiabetic subjects, but this defect could be
overcome by increasing the plasma insulin concentration. NIDDM patients showed
normal sensitivity to the inhibitory action of insulin on FFA metabolism;
however, maximal suppression by insulin was impaired. The combination of obesity
and NIDDM was associated with a further enhancement of reesterification of FFA
than observed in either condition alone. In both obesity and NIDDM, the
dose-response curve for suppression of hepatic glucose production by insulin was impaired. While obesity was primarily characterized by reduced sensitivity to the stimulatory action of insulin on oxidative and nonoxidative pathways of glucose metabolism, resistance to the effect of insulin on glucose metabolism in NIDDM was characterized by a reduced maximal response. The combination of obesity and NIDDM further impaired the sensitivity of liver glucose output and glucose oxidation to insulin. The hypothesis is advanced that in uncomplicated obesity, increased availability and oxidation of FFA leads, by the FFA/glucose cycle, to the impairment in glucose utilization. In NIDDM, on the other hand, the defect in glucose utilization is primary, and the enhanced rate of FFA oxidation may represent a compensatory phenomenon
Obesity and insulin resistance in humans: a dose-response study
No full textInsulin-mediated glucose metabolism (euglycemic insulin clamp at plasma insulin concentration of 100 microU/mL) and glucose-stimulated insulin secretion (hyperglycemic clamp) were examined in 42 obese subjects (ideal body weight [IBW], 158 +/- 4%) with normal glucose tolerance and in 36 normal weight (IBW, 102% +/- 1%) age-matched controls. In 10 obese and eight control subjects, insulin was infused at six rates to increase plasma insulin concentration by approximately 10, 20, 40, 80, 2,000, and 20,000 microU/mL. Throughout the physiologic range of plasma insulin concentrations, both the increase in total body glucose uptake and the suppression of hepatic glucose production (HGP) were significantly impaired in the obese group (P less than .001 to .01). At the two highest plasma insulin concentrations, inhibition of HGP and the stimulation of glucose disposal were similar in both the obese and control groups. Insulin secretion during the hyperglycemic (+/- 125 mg/dL) clamp was twofold greater in obese subjects than in controls (P less than .01) and was inversely related to the rate of glucose uptake during the insulin clamp (r = -.438, P less than .05), but was still unable to normalize glucose disposal (P less than .05). In conclusion, our results indicate that insulin resistance is a common accompaniment of obesity and can be overcome at supraphysiological insulin concentrations. Both in the basal state and following a hyperglycemic stimulus obese people display hyperinsulinemia, which correlates with the degree of insulin resistance. However, endogenous hyperinsulinemia fails to fully compensate for the insulin resistance
In vivo glucose metabolism in obese and type II diabetic subjects with or without hypertension
No full textThis study examined whether the presence of hypertension, an insulin-resistant condition, exacerbates the defect in insulin action observed in obesity and type II diabetes mellitus. Glucose metabolism in the basal state and in response to insulin was quantitated by using the euglycemic insulin (20 mU.min-1 x m-2) clamp in combination with 3-[3H]glucose infusion and indirect calorimetry in 20 obese nondiabetic subjects (10 hypertensive and 10 normotensive), 26 type II diabetic subjects (13 hypertensive and 13 normotensive), and 11 normal nondiabetic subjects. The two groups of obese subjects and the two groups of diabetic subjects were matched for sex, age, race, body mass index, and fat distribution. Both in the basal state and during insulin infusion, glucose disposal rates (total, oxidative, and nonoxidative) were similar in obese subjects with or without hypertension. Compared with control subjects, both groups of obese subjects were markedly insulin resistant. Similarly, type II diabetic individuals, whether normotensive or hypertensive, were equally insulin resistant. The severity of insulin resistance was nearly identical in obese and diabetic groups. In diabetic subjects, the inhibitory effect of insulin on hepatic glucose output, lipolysis, and lipid oxidation was blunted compared with normal subjects. In obese subjects the ability of insulin to inhibit lipolysis and lipid oxidation was impaired. However, hypertension did not alter the suppressive effects of insulin on hepatic glucose production, plasma free fatty acid levels, or lipid oxidation in either obese or type II diabetic subjects. These results indicate that hypertension does not confer a greater severity of insulin resistance than that already is present in obesity and type II diabetes mellitus
Characterization of cellular defects of insulin action in Type 2 (non-insulin-dependent) diabetes mellitus
No full textSeven non-insulin-dependent diabetes mellitus (NIDDM) patients participated in three clamp studies performed with [3-3H]- and [U-14C]glucose and indirect calorimetry: study I, euglycemic (5.2 +/- 0.1 mM) insulin (269 +/- 39 pM) clamp; study II, hyperglycemic (14.9 +/- 1.2 mM) insulin (259 +/- 19 pM) clamp; study III, euglycemic (5.5 +/- 0.3 mM) hyperinsulinemic (1650 +/- 529 pM) clamp. Seven control subjects received a euglycemic (5.1 +/- 0.2 mM) insulin (258 +/- 24 pM) clamp. Glycolysis and glucose oxidation were quantitated from the rate of appearance of 3H2O and 14CO2; glycogen synthesis was calculated as the difference between body glucose disposal and glycolysis. In study I, glucose uptake was decreased by 54% in NIDDM vs. controls. Glycolysis, glycogen synthesis, and glucose oxidation were reduced in NIDDM patients (P < 0.05-0.001). Nonoxidative glycolysis and lipid oxidation were higher. In studies II and III, glucose uptake in NIDDM was equal to controls (40.7 +/- 2.1 and 40.7 +/- 1.7 mumol/min.kg fat-free mass, respectively). In study II, glycolysis, but not glucose oxidation, was normal (P < 0.01 vs. controls). Nonoxidative glycolysis remained higher (P < 0.05). Glycogen deposition increased (P < 0.05 vs. study I), and lipid oxidation remained higher (P < 0.01). In study III, hyperinsulinemia normalized glycogen formation, glycolysis, and lipid oxidation but did not normalize the elevated nonoxidative glycolysis or the decreased glucose oxidation. Lipid oxidation and glycolysis (r = -0.65; P < 0.01), and glucose oxidation (r = -0.75; P < 0.01) were inversely correlated. In conclusion, in NIDDM: (a) insulin resistance involves glycolysis, glycogen synthesis, and glucose oxidation; (b) hyperglycemia and hyperinsulinemia can normalize total body glucose uptake; (c) marked hyperinsulinemia normalizes glycogen synthesis and total flux through glycolysis, but does not restore a normal distribution between oxidation and nonoxidative glycolysis; (d) hyperglycemia cannot overcome the defects in glucose oxidation and nonoxidative glycolysis; (e) lipid oxidation is elevated and is suppressed only with hyperinsulinemia
Estimation of blood flow heterogeneity distribution in human skeletal muscle from positron emission tomography data.
No full textRegional blood flow distribution in animal skeletal muscle is markedly uneven at rest and during various physiological states (exercise and hyperemia). It has been hypothesized that the vasodilatory properties of insulin may concur with insulin action on the myocite in determining stimulation of muscle glucose metabolism in vivo. In this study, we developed a method to determine noninvasively both bulk flow and regional flow heterogeneity in human skeletal muscle. Positron emission tomography studies with [15O] water were performed in seven normal subjects, both in the basal state and after 1 hr of euglycemic hyperinsulinemia. Hyperinsulinemia almost doubled skeletal muscle blood flow, but apparently did not affect the relative dispersion, the skewness, or the kurtosis of the flow distribution. However, the regression line between basal and insulin-stimulated flow values showed a nonzero intercept, and the relationship between basal flow and its insulin-stimulated fractional change was hyperbolic. These findings suggest that insulin vasodilated proportionally more the areas with the lowest basal perfusion values. These are the first data to demonstrate that in human skeletal muscle: (i) blood flow is heterogeneous; and (ii) insulin, although doubling muscle bulk flow, does not affect the relative dispersion of its distribution. This result implies that regional redistribution of perfusion is not involved in determining the metabolic response of skeletal muscle to insulin. Yet, since insulin vasodilates proportionally more the less perfused areas, it still exerts an optimizing effect on flow distribution in human muscle
- …
