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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously demonstrated that hyperinsulinemia can amplify the counterregulatory response to hypoglycemia in normal subjects. The aim of the present study was to determine if differing concentrations of insulin can modify the counterregulatory response to equivalent fixed hypoglycemia in insulin-dependent-diabetic subjects (IDDM). Experiments were carried out in seven lean, overnight-fasted, moderately controlled (hemoglobin A1c, 10.9%; normal range, 5-9) IDDM subjects with a disease duration of 13 +/- 3 yr. All were maintained normoglycemic overnight so that basal plasma glucose (5.6 +/- 0.2 and 5.4 +/- 0.2 mmol/L) and insulinemia (63 +/- 18 and 48 +/- 10 pmol/L) were similar at the start of each study. Insulin was infused for 120 min in two separate randomized protocols, so that steady state levels (mean +/- SE) of 742 +/- 212 pmol/L (low) and 3360 +/- 710 pmol/L (high) were obtained. Glucose was infused during both protocols to ensure that the rate of fall of plasma glucose (0.09 mmol/L.min) and the hypoglycemic plateau (2.8 +/- 0.1 mmol/L) were similar. In response to hypoglycemia, plasma levels of epinephrine, norepinephrine, cortisol, GH, and pancreatic polypeptide increased similarly during both insulin infusions. During the final 30 min, despite similar levels of counterregulatory hormones, hepatic glucose production was significantly reduced in the presence of high compared to low insulin levels (1.7 +/- 2.8 vs. 8.3 +/- 1.7 mumol/kg.min; P < 0.05). Similarly, plasma nonesterified fatty acids (472 +/- 94 vs. 787 +/- 105 mumol/L) and blood 3-hydroxybutyrate levels (30 +/- 12 vs. 106 +/- 29 mumol/L) were significantly reduced (P < 0.05) during high compared to low dose infusions. Cardiovascular parameters (heart rate and systolic, diastolic, and mean arterial pressures) responded similarly during both infusions. We conclude that 1) insulin per se does not amplify the counterregulatory response to equivalent hypoglycemia in individuals with moderately controlled, long duration IDDM; and 2) there may be a relative autonomic adrenomedullary deficit in some IDDM subjects that prevents the amplified epinephrine response to hyperinsulinemia during hypoglycemia.
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PMID:The effects of insulin on the counterregulatory response to equivalent hypoglycemia in patients with insulin-dependent diabetes mellitus. 807 24

Hyperinsulinemia is very much in the spotlight. Debate rages as to its significance and role in the etiology not only of NIDDM, but also other morphological and metabolic risk factors for atherosclerotic cardiovascular disease, including upper-body obesity, dyslipidemia, hypertension, and hyperuricemia. Epidemiological data support a key role for hyperinsulinemia in these disorders but it is far from conclusive except for the fact that hyperinsulinemia and insulin resistance may be present many years before the onset of impaired glucose tolerance and NIDDM, and clearly play a role in their etiology. The thrifty genotype hypothesis provides a plausible basis for a better understanding of how hyperinsulinemia and insulin resistance could lead to glucose intolerance and atherosclerotic cardiovascular disease, but the detailed biochemical mechanisms remain elusive. A role for increased sympathetic nervous system activity, resulting from hypothalamic stimulation as a primary event causing hyperinsulinemia, cannot be excluded as a cause of hyperinsulinemia. The current focus on hyperinsulinemia also has resulted in closer examination of the therapy of diabetes and hypertension, emphasizing the need to avoid hyperinsulinemia in both IDDM and NIDDM individuals because of the putative risk of atherosclerotic cardiovascular disease and hypertension. There is still a paucity of epidemiological data to support a role for hyperinsulinemia in the etiology of hypertension. However, clinical practice already is being influenced by the fact that ACE inhibitors have been shown to reduce insulin resistance in clinical research studies. The research reviewed here, particularly that relating to hyperinsulinemia, insulin resistance, and cardiovascular disease risk factors, has opened new vistas for the treatment and prevention of NIDDM and atherosclerotic cardiovascular disease. Appropriate exercise clearly is associated with improved insulin sensitivity, modification of CVD risk factors, and lower prevalence of NIDDM. Upper-body obesity, the latest culprit in the field, can also be reduced by exercise. Hyperinsulinemia and insulin resistance can be detected in children, adolescents, and young adults. NIDDM can be prevented, but clearly, intervention needs to commence in childhood, and intensive risk factor intervention in subjects with NIDDM can reduce the risk of atherosclerotic cardiovascular disease. It seems paradoxical that prevention of NIDDM and atherosclerotic cardiovascular disease are now possible even though the biochemical and molecular basis of these disorders is not fully understood.
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PMID:Hyperinsulinemia--how innocent a bystander? 829 79

A major problem in replacing insulin in type I diabetes mellitus is that currently no depot preparation exists that is capable of mimicking the background insulin secretion of the healthy pancreas. Because all of the currently available intermediate- or long-acting insulin preparations have a peaked-action profile, excess insulin action at midnight and insulin waning at dawn occur whenever such an insulin preparation is given at supper time. If the target fasting plasma glucose is the ambitious near-normoglycemia of intensive insulin therapy, intermediate-acting insulin at suppertime easily results in hypoglycemia in the early evening hours and hyperglycemia in the fasting state. The problems of overnight glycemia in type I diabetes are further complicated by the dawn phenomenon and the Somogyi phenomenon. The dawn phenomenon is the combination of an initial decrease in insulin requirements between approximately 2400 and approximately 0300, followed by an increase in the insulin needs between approximately 0500 and approximately 0800. The dawn phenomenon is the result of changes in hepatic (and extrahepatic) insulin sensitivity, which are best attributed to nocturnal growth hormone secretion. The dawn phenomenon is a day-to-day reproducible event that occurs in nearly all diabetic patients. Its contribution to fasting hyperglycemia correlates with diabetes duration (inversely) and the HbA1c percentage (directly). Overall, it is estimated that the specific contribution of the dawn phenomenon to fasting hyperglycemia is approximately 2 mM (approximately 35 mg/dl), but it may be much greater because of the warning of the depot-insulin preparation injected the previous evening. The Somogyi phenomenon, strictly speaking, refers to fasting hyperglycemia that occurs after inducement of nocturnal hypoglycemia by regular insulin. Because the present therapeutic regimens of NPH/Lente insulin given at suppertime cause overnight hyperinsulinemia, excessive fasting hyperglycemia rarely follows nocturnal hypoglycemia, except when excessive glucose is ingested to correct hypoglycemia. However, nocturnal hypoglycemia may easily deteriorate glycemic control later in the day, because it induces prolonged posthypoglycemic insulin resistance, which results in postbreakfast and late-morning hyperglycemia. With nocturnal insulin therapy, it is important to consider the problems of insulin pharmacokinetics, the dawn phenomenon, and the Somogyi phenomenon to prevent both nocturnal hypoglycemia and excessive fasting hyperglycemia.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Nocturnal blood glucose control in type I diabetes mellitus. 829 80

Sodium retention has been advocated to give rise to hypertension in humans. Increases in blood glucose and insulin concentrations ensue in the stimulation of sodium reabsorption by the kidney. Although the combined occurrence of hyperglycemia and hyperinsulinemia, frequently secondary to insulin resistance with regard to carbohydrate metabolism, is a hallmark of non-insulin dependent diabetes (NIDDM), the role of these abnormalities in determining an impaired natriuresis in NIDDM is not yet fully understood. We studied sodium homeostasis in 14 control subjects and 59 NIDDM normotensive, normoalbuminuric patients who were divided into two groups with markedly impaired (Group 2 NIDDM: 30) and less severely impaired (Group 1 NIDDM: 29) insulin sensitivity during euglycemic-hyperinsulinemic (80 to 90 microU/ml plasma insulin) clamp. A hyperglycemic (9 mmol/liter plasma glucose)--nearly euinsulinemic (20 to 40 microU/ml plasma insulin) clamp was also performed in the same 14 controls and in two cohorts of 22 Group 2 and 17 Group 1 NIDDM patients. The two groups of patients had similar overnight fasting glucose levels (Group 1 NIDDM vs. Group 2 NIDDM: 176 +/- 13 vs. 185 +/- 15 mg/dl, mean +/- SE). Conversely, overnight fasting plasma insulin was significantly higher in Group 2 NIDDM than in Group 1 NIDDM patients (Group 1 NIDDM vs. Group 2 NIDDM: 12 +/- 3 vs. 18 +/- 3 microU/ml, P < 0.05). Both NIDDM Groups had higher plasma glucose and insulin than controls (75 +/- 4 mg/dl and 6 +/- 3 microU/ml). Blood pressure levels and albumin excretion rates were slightly but significantly higher in Group 2 NIDDM, but not in Group 1 NIDDM patients, than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of hyperglycemia and insulin resistance in determining sodium retention in non-insulin-dependent diabetes. 835 55

IDDM subjects lose the ability to release glucagon during hypoglycemia. Because replacement of basal levels of amino acids enhances the glucagon response to hypoglycemia in healthy subjects, we tested whether raising amino acid levels during hypoglycemia could reverse the defective alpha-cell response in IDDM patients. For this purpose, 11 IDDM patients (HbA1 9.4 +/- 0.6%) and 8 healthy, nondiabetic subjects received two hypoglycemic insulin clamp studies (0.8 mU.kg-1 x min-1) in which plasma glucose was clamped at 55 mg/dl (3.08 mM) for 180 min. During one of the studies, an infusion of amino acids was superimposed between 120 and 180 min (0.3 g.kg-1 x h-1). This dose of amino acids had a small effect on plasma glucagon levels during euglycemic hyperinsulinemia that was comparable in normal and IDDM subjects. In healthy control subjects, plasma glucagon rose by 80% during the initial hypoglycemic phase of the study. The addition of amino acids produced a further sharp (200-250 ng/L, P < 0.02) rise in plasma glucagon, such a change did not occur in the absence of amino acids. In contrast, plasma glucagon in IDDM patients failed to increase during hypoglycemia alone and rose by only 40-50 ng/L (P < 0.05 vs. controls) when amino acid infusion was superimposed, even though plasma amino acid levels rose to the same extent in IDDM and control subjects. More importantly, the rise in glucagon produced by amino acids was comparable during hypoglycemic and euglycemic hyperinsulinemia in the IDDM patients, results strikingly different from those observed in nondiabetic control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Loss of potentiating effect of hypoglycemia on the glucagon response to hyperaminoacidemia in IDDM. 845 5

We evaluated the effect of physiologic hyperinsulinemia (plasma insulin 329 +/- 62 vs 687 +/- 62 pmol/L) on counterregulatory hormone responses in 8 IDDM subjects studied during a 2-hour hypoglycemic clamp study with an equivalent degree of hypoglycemia (plasma glucose 3.1 +/- 0.1 and 3.0 +/- 0.1 mmol/L, respectively). Plasma epinephrine levels were increased by 71% during the last 60 minutes of hypoglycemia in the high insulin study (840 +/- 180 vs 1440 +/- 310 pmol/L, respectively p = 0.006). In addition, plasma cortisol and norepinephrine were also increased in the high insulin study (by 19% and 24% respectively, p < 0.01, for both). Plasma growth hormone and glucagon concentrations were not altered by high dose insulin infusion. In spite of increased epinephrine secretion, the glucose infusion rate required to maintain glucose was 2-fold greater in the high insulin study, and there was greater suppression of lipolysis in that group. We conclude that hyperinsulinemia may enhance counterregulatory hormone secretion in IDDM.
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PMID:Physiologic hyperinsulinemia enhances counterregulatory hormone responses to hypoglycemia in IDDM. 849 33

The prevalence of hypertension in diabetes is significantly higher than in non-diabetics, perhaps twice as common. The excess is related to diabetic nephropathy, mainly in type 1 diabetes, to obesity, mainly in type 2 diabetes, but also to increased sympathetic activity. Furthermore, the increased prevalence of hypertension may relate to insulin resistance and its sequelae. Insulin resistance leads to hyperinsulinemia, relates to increased LDL and reduced HDL levels, causes the development of impaired glucose tolerance and type 2 diabetes and might also be causally related to the onset of hypertension. Syndrome X has relevant therapeutic implications in the management of hypertension. Hypertension is a major risk factor for large vessel disease in diabetics and also a risk factor for microangiopathy, particularly nephropathy. The incidence of atherosclerotic disease is dramatically increased in both type 1 and type 2 diabetics and is the major cause of morbidity and premature death mainly in patients with raised urinary albumin excretion. Thus, diabetics show a two-fold increased risk of coronary heart disease, 2-6 fold increased risk of stroke and a several-fold increased risk of peripheral vessel disease. Some evidence suggests that hypertension may be a risk factor for retinopathy, particularly its progression, but surely hypertension is a significant risk factor for nephropathy, accelerating its progression and perhaps even causing the onset of the glomerulopathy. The mechanisms by which hypertension might contribute to the evolution of both large vessel as well as small vessel disease is still unknown, although increased capillary leakage and vascular endothelium alterations might be important factors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Hypertension and diabetes]. 856 58

To assess the effect of pancreas transplantation on free fatty acid (FFA) and glucose metabolism, we studied seven uremic IDDM patients (HbA1c 9.1%), nine IDDM patients after combined kidney-pancreas transplantation (HbA1c 5.8%), seven patients with chronic uveitis (HbA1c 5.6%), and nine normal control subjects (HbA1c 5.5%) by means of the [3(- 3)H]glucose and [1(-14)C]palmitate infusion techniques combined with indirect calorimetry and euglycemic insulin clamp. In the postabsorptive state, pancreas-transplant patients had similar plasma glucose and FFA concentrations and non-statistically different rates of hepatic glucose production (HGP) and FFA turnover, while demonstrating a reduced rate of FFA oxidation (42 +/- 5 vs. 73 +/- 10 micromol x m-2 x min-1; P < 0.05) compared with control subjects. After 180 min of tracer equilibration, all subjects underwent a low-dose (100 min, 8 mU x m-2 x min-1) followed by a high-dose (100 min, 40 mU x m-2 x min-1) euglycemic insulin infusion. During insulin infusion, pancreas-transplant patients showed a greater inhibition of FFA concentration (609 +/- 76 to 58 +/- 15 micromol/l) compared with healthy subjects (681 +/- 90 to 187 +/- 25 micromol/l; P < 0.01 vs. pancreas-transplant patients). FFA turnover and oxidation rates during both low-dose and high-dose insulin infusions were lower in pancreas-transplant patients compared with healthy subjects (P < 0.03 and P < 0.01, for turnover and oxidation, respectively). Uremic IDDM patients demonstration altered basal and insulin-mediated glucose metabolism. Pancreas transplantation normalized only insulin-mediated glucose oxidation, leaving the stimulation of non-oxidative glucose disposal still markedly defective. In conclusion, patients after pancreas transplantation have normal basal FFA turnover and reduced basal FFA oxidation rates. During hyperinsulinemia, pancreas-transplant patients show a normal inhibition of FFA turnover and FFA oxidation. Insulin-mediated glucose metabolism remained abnormal after pancreas transplantation. Our findings may be related to the effect of chronic immunosuppressive therapy on glucose and FFA metabolism.
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PMID:Effect of pancreas transplantation on free fatty acid metabolism in uremic IDDM patients. 859 42

The present study examines the effect of the route of insulin delivery on glucose turnover in humans. By using a new noninvasive in vivo method, the acute effect of insulin secreted by the pancreas can be compared with that of insulin delivered by a peripheral vein. Three euglycemic-hyperinsulinemic studies were performed in lean healthy men. In the first study (n = 10), constant portal hyperinsulinemia was produced using a programmed intravenous tolbutamide infusion algorithm, and the insulin secretion rate was mathematically derived by deconvolution from peripheral plasma C-peptide levels. In the second study (n = 10), exogenous insulin was infused by peripheral vein at the same rate as that determined in the first study. In the third study (n = 7), the peripheral insulin levels in the first study were matched by infusing exogenous insulin into a peripheral vein at half that rate. Peripheral insulin levels were higher (P < 0.001) with the full-rate peripheral insulin infusion (266.3 +/- 28.1 pmol/l) than with the portal delivery of insulin (171.1 +/- 30.4 pmol/l) or the half-rate peripheral insulin infusion (158.6 +/- 7.4 pmol/l) (portal versus half-rate peripheral insulin infusion, NS). Calculated hepatic insulin levels were higher (P < 0.001) in the portal insulin study (443.1 +/- 52.6 pmol/l) than in the full-rate peripheral insulin study (303.6 +/- 30.9 pmol/l) or in the half-rate peripheral insulin study (204.5 +/- 9.8 pmol/l). Hepatic glucose production (HGP) was suppressed to a greater extent with the full-rate peripheral insulin infusion (69.3 +/- 7.8%, P < 0.001 vs. portal or half-rate peripheral insulin) than portal (50.3 +/- 9.8%) or half-rate peripheral insulin infusion (36.8 +/- 3.8%). In the portal insulin study, however, suppression was greater than in the half-rate peripheral insulin study (P < 0.01), in spite of equal peripheral insulin levels. The assumption that tolbutamide, when used in this fashion, has no independent effect on glucose turnover, glucagon, or gluconeogenic precursor and energy substrates for gluconeogenesis was validated in five C-peptide-negative patients with IDDM. We conclude that in nondiabetic humans, 1) peripheral effects of insulin are important in suppressing HGP, as evidenced by the greater suppression of HGP with equivalent rate peripheral versus portal insulin delivery, and 2) because HGP was suppressed to a greater extent with portal verus peripheral insulin delivery at half the rate when peripheral insulin levels were matched, insulin-induced suppression of HGP is also partly mediated by a direct hepatic effect.
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PMID:Hepatic glucose production is regulated both by direct hepatic and extrahepatic effects of insulin in humans. 860 67

Hyperinsulinemia. is associated with an overexpression of mRNA for the ob protein leptin in rodent models of genetic obesity, and insulin has been reported to directly stimulate leptin mRNA in rat adipocytes. Human obesity is also associated with increased leptin mRNA as well as plasma levels, but there have been no reports of the effect of insulin on leptin secretion. We, therefore, tested the hypothesis that insulin stimulates leptin secretion in humans. Using a newly developed leptin assay, immunoreactive leptin was measured in fasting and postprandial plasma samples from 27 healthy adults and in samples before and during euglycemic-hyperinsulinemic then stepped hypoglycemic (hourly steps at 85, 75, 65, 55, and 45 mg/dl) clamps from 10 healthy subjects and 11 patients with IDDM. Plasma leptin was correlated (r = 0.84, P = 0.0005) with BMI in obese but not nonobese subjects and with fasting (r = 0.75, P = 0.008) but not postprandial plasma insulin levels. (Leptin levels did not change postprandially.) Euglycemic hyperinsulinemia did not alter leptin levels, nor did hyperinsulinemic hypoglycemia. Thus, because circulating leptin levels are not increased during postprandial hyperinsulinemia or during euglycemic (or hypoglycemic) hyperinsulinemia, we conclude that, at least in the short term, insulin does not increase leptin secretion in humans and that hyperleptinemia in obese individuals is not likely the result of hyperinsulinemia.
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PMID:Plasma leptin and insulin relationships in obese and nonobese humans. 862 Oct 26


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