Fasting Hyperglycemia In Type Research Articles

Diurnal rhythm in endogenous glucose production is a major contributor to fasting hyperglycaemia in type 2 diabetes. Suprachiasmatic deficit or limit cycle behaviour?

An increase in endogenous glucose production (EGP) is a major contributor to fasting morning hyperglycaemia in type 2 diabetes. This increase is dissipated with fasting, later in the day. To understand its origin, EGP, gluconeogenesis and hormones that regulate metabolism were measured over 24 h. We hypothesised that EGP, and therefore glycaemia, would demonstrate a centrally mediated circadian rhythm in type 2 diabetes. Seven subjects with type 2 diabetes and six age- and BMI-matched control subjects, fasting after breakfast (08.00 h), underwent a further 24-h fast, with the infusion of [U-(13)C]glucose and [3-(14)C]lactate, starting at 14.00 h. The MCR and production of total and gluconeogenic glucose were determined from the tracer concentrations using compartmental analysis. MCR was near constant: 1.73+/-0.10 in control and 1.40+/-0.14 ml kg(-1) min(-1) in diabetic subjects (p=0.04). EGP in diabetes rose gradually overnight from 8.2+/-0.7 to 11.3+/-0.5 micromol kg(-1) min(-1) at 06.00 h (p<0.05). Glucose utilisation lagged EGP, rising from 8.5+/-0.6 to 10.5+/-0.4 micromol kg(-1) min(-1) (p<0.05), inducing a fall in glycaemia from a peak of 8.0+/-0.5 mmol/l to 6.3+/-0.4 mmol/l (p<0.05). Cortisol and melatonin showed diurnal variations, whereas insulin, glucagon and leptin did not. Melatonin was most closely related to EGP, but its secretion was attenuated in diabetes (p<0.05). In type 2 diabetes, EGP and gluconeogenesis display diurnal rhythms that drive the fasting hyperglycaemia and are absent in healthy control subjects. The rise in EGP may be related to a deficit in suprachiasmatic nucleus activity in diabetes, or result from non-linear behaviour plus a transition from a normal steady state to a limit cycle pattern in diabetes, or both.

Contribution of elevated free fatty acid levels to the lack of glucose effectiveness in type 2 diabetes.

Increased circulating free fatty acids (FFAs) inhibit both hepatic and peripheral insulin action. Because the loss of effectiveness of glucose to suppress endogenous glucose production and stimulate glucose uptake contributes importantly to fasting hyperglycemia in type 2 diabetes, we examined whether the approximate twofold elevations in FFA characteristic of poorly controlled type 2 diabetes contribute to this defect. Glucose levels were raised from 5 to 10 mmol/l while maintaining fixed hormonal conditions by infusing somatostatin with basal insulin, glucagon, and growth hormone. Each individual was studied at two FFA levels: with (NA+) and without (NA-) infusion of nicotinic acid in nine individuals with poorly controlled type 2 diabetes (HbA(1c) = 10.1 +/- 0.7%) and with (LIP+) and without (LIP-) infusion of lipid emulsion in nine nondiabetic individuals. Elevating FFA to approximately 500 micro mol/l blunted the ability of glucose to suppress endogenous glucose production (LIP- = -48% vs. LIP+ = -28%; P < 0.01) and increased glucose uptake (LIP- = 97% vs. LIP+ = 51%; P < 0.01) in nondiabetic individuals. Raising FFA also blunted the endogenous glucose production response in 10 individuals with type 2 diabetes in good control (HbA(1c) = 6.3 +/- 0.3%). Conversely, normalizing FFA nearly restored the endogenous glucose production (NA- = -7% vs. NA+ = -41%; P < 0.001) and glucose uptake (NA- = 26% vs. NA+ = 64%; P < 0.001) responses to hyperglycemia in individuals with poorly controlled type 2 diabetes. Thus, increased FFA levels contribute substantially to the loss of glucose effectiveness in poorly controlled type 2 diabetes.

Phosphoenolpyruvate Carboxykinase Overexpression Selectively Attenuates Insulin Signaling and Hepatic Insulin Sensitivity in Transgenic Mice

The ability of insulin to suppress gluconeogenesis in type II diabetes mellitus is impaired; however, the cellular mechanisms for this insulin resistance remain poorly understood. To address this question, we generated transgenic (TG) mice overexpressing the phosphoenolpyruvate carboxykinase (PEPCK) gene under control of its own promoter. TG mice had increased basal hepatic glucose production (HGP), but normal levels of plasma free fatty acids (FFAs) and whole-body glucose disposal during a hyperinsulinemic-euglycemic clamp compared with wild-type controls. The steady-state levels of PEPCK and glucose-6-phosphatase mRNAs were elevated in livers of TG mice and were resistant to down-regulation by insulin. Conversely, GLUT2 and glucokinase mRNA levels were appropriately regulated by insulin, suggesting that insulin resistance is selective to gluconeogenic gene expression. Insulin-stimulated phosphorylation of the insulin receptor, insulin receptor substrate (IRS)-1, and associated phosphatidylinositol 3-kinase were normal in TG mice, whereas IRS-2 protein and phosphorylation were down-regulated compared with control mice. These results establish that a modest (2-fold) increase in PEPCK gene expression in vivo is sufficient to increase HGP without affecting FFA concentrations. Furthermore, these results demonstrate that PEPCK overexpression results in a metabolic pattern that increases glucose-6-phosphatase mRNA and results in a selective decrease in IRS-2 protein, decreased phosphatidylinositol 3-kinase activity, and reduced ability of insulin to suppress gluconeogenic gene expression. However, acute suppression of HGP and glycolytic gene expression remained intact, suggesting that FFA and/or IRS-1 signaling, in addition to reduced IRS-2, plays an important role in downstream insulin signal transduction pathways involved in control of gluconeogenesis and progression to type II diabetes mellitus.

Role of the kidney in hyperglycemia in type 2 diabetes.

Overproduction of glucose is the major factor responsible for fasting hyperglycemia in type 2 diabetes. Formerly, this had been considered to be solely due to excessive hepatic glucose production because the human kidney was not regarded as an important source of glucose except during acidosis and after prolonged fasting. However, data accumulated over the last 60 years in animal and in vitro studies have provided considerable evidence that the kidney plays an important role in glucose homeostasis in conditions other than acidosis and prolonged fasting. This article summarizes early work in animals and humans, discusses methodologic issues in assessing renal glucose release in vivo, and provides evidence from recent human studies that the kidney substantially contributes to glucose overproduction in type 2 diabetes.

Production and metabolic clearance of glucose under basal conditions in Type II (non-insulin-dependent) diabetes mellitus.

The pathogenesis of fasting hyperglycaemia in Type II (non-insulin-dependent) diabetes mellitus has yet to be clarified. Rates of glucose production (Ra), utilization and metabolic clearance rate were therefore measured during an extended fast, in control subjects and in Type II diabetic patients. Nine subjects with newly-diagnosed or diet-treated diabetes and seven control subjects matched for age and weight (BMI 36.0 +/- 2.4 and 35.3 +/- 3.1 kg/m2 respectively) underwent an overnight fast followed by a 10-h unprimed infusion of [6-3H]glucose. Plasma tracer concentrations were fitted by a single-compartment model. The metabolic clearance rate was near-constant [61.7 + 2.4 ml/(min-m2)] in diabetic patients and [75.5 +/- 3.3 ml/(min-m2)] in control subjects (p < 0.05). It was correlated to the glucose concentrations both at t = 0 (r = -0.752, p = 0.0008) and t = 10 h (r = -0.675, p = 0.004). The calculated volume of distribution was 17.3 +/- 1.4 l (18.2 % weight, diabetes), 19.6 +/- 2.4 l (18.4 % weight, control). Glycaemia fell from 10.7 +/- 0.8 mmol/l to 6.5 +/- 0.3 mmol/l by 10 h (p < 0.05) in diabetes and from 5.6 +/- 0.6 to 4.8 +/- 0.1 mmol/l in control subjects (p < 0.05). The rate of glucose production decreased in parallel, from 563 +/- 33 to 363 +/- 23 micromol/(min-m2) (p < 0.05) in diabetes from 419 +/- 20 to 347 +/- 32 micromol/(min-m2) in control subjects. Initial Ra was higher in diabetic patients than in control subjects (p < 0.05) and was highly correlated to glycaemia (r = 0.836, p = 0.0001). By 10 h, Ra had converged in diabetic patients and control subjects and all correlation with glycaemia was lost (r = 0.0017, p = 0.95). In relatively early diabetes, the more "labile" portion of fasting hyperglycaemia, which subsequently decreased, was closely related to the simultaneously decreasing Ra. The 25 % increase in glucose concentrations which persisted as stabilized Ra, resulted from about a 20 % lower metabolic clearance rate.

Erythromycin reduces fasting hyperglycaemia in type 2 diabetes

Erythromycin reduces fasting hyperglycaemia in type 2 diabetes

Role of hepatic glucose production and glucose uptake in the pathogenesis of fasting hyperglycemia in type 2 diabetes: normalization of glucose kinetics by short-term fasting

Role of hepatic glucose production and glucose uptake in the pathogenesis of fasting hyperglycemia in type 2 diabetes: normalization of glucose kinetics by short-term fasting

Role of hepatic glucose production and glucose uptake in the pathogenesis of fasting hyperglycemia in type 2 diabetes: normalization of glucose kinetics by short-term fasting.

The relative impact of hepatic glucose production (HGP) and peripheral glucose uptake (GU) on plasma glucose concentration was assessed in 54 noninsulin-dependent diabetes mellitus (NIDDM) and 50 control subjects submitted to a variable period of fasting (14-108 h) with special focus on the normal and low hyperglycemic range. Within each population we found a highly significant (P < 0.001) positive correlation between plasma glucose concentration and HGP in the whole range of glycemia, but the slope of the regression line was steeper (P < 0.001) in the diabetic than in the control group. The two curves intersected at a glucose level of 4.0 mmol/L. Therefore, for a given HGP rate above the intersection point, diabetic patients had a higher plasma glucose concentration than nondiabetic individuals, owing to an approximately 15% reduction (P < 0.025) in the metabolic clearance rate, despite the fact that the plasma insulin level was 2-fold higher (P < 0.05) in the diabetic patients. When diabetic and nondiabetic subjects were compared at a similar low glucose level of 4.0 mmol/L brought about by short-term fasting, all parameters of glucose kinetics were identical in both groups. We thus conclude that 1) HGP is the major determinant of plasma glucose concentration in control as well as in diabetic subjects whatever the nutritional state; 2) the slight hyperglycemia prevailing in mild NIDDM results from the combination of an impaired insulin-induced inhibition of HGP and stimulation of GU because both parameters are inappropriately normal in the face of elevated plasma glucose and insulin levels; and 3) the normalization of GU and HGP after short-term fasting suggests that pathways of noninsulin-mediated GU operate in a normal way in NIDDM.

Nocturnal blood glucose control in type I diabetes mellitus.

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)

Fasting hyperglycemia in type I diabetes mellitus

The differential diagnosis of fasting hyperglycemia in type I diabetes includes the Somogyi effect, the dawn phenomenon, and insufficient insulin administration. To determine the causes of fasting hyperglycemia and their effect on subsequent daytime blood glucose control, the authors retrospectively reviewed blood glucose profiles of 126 patients with type I diabetes. The Somogyi effect accounted for 12.6% of all instances of fasting hyperglycemia, the dawn phenomenon, 24.1%, and poor control, 63.3%. Measurement of 3 AM and 5 AM blood glucose values is the key to making a correct diagnosis. Once a patient's fasting hyperglycemia is placed in one of these groups, appropriate treatment can be started.

Insulin resistance, but normal basal rates of glucose production in patients with newly diagnosed mild diabetes mellitus

Fasting hyperglycemia in Type II (non-insulin-dependent) diabetes has been suggested to be due to hepatic overproduction of glucose and reduced glucose clearance. We studied 22 patients (10 lean and 12 obese) with newly diagnosed mild diabetes mellitus (fasting plasma glucose less than 15 mmol/l, urine ketone bodies less than 1 mmol/l), and two age- and weight-matched groups of non-diabetic control subjects. Glucose turnover rates and sensitivity to insulin were determined using adjusted primed-continuous [3-3H]glucose infusion and the hyperinsulinemic euglycemic clamp technique. Insulin-stimulated glucose utilization was reduced in both diabetic groups (lean patients: 313 +/- 35 vs 531 +/- 22 mg.m-2.min-1, p less than 0.01; obese patients: 311 +/- 28 vs 453 +/- 26 mg.m-2.min-1, p less than 0.01). Basal plasma glucose concentrations decreased 0.43 +/- 0.05 mmol/l per h (p less than 0.01). Glucose production rates were smaller than glucose utilization rates (lean patients: 87 +/- 3 vs 94 +/- 3 mg.m-2.min-1, p less than 0.01; obese patients: 79 +/- 5 vs 88 +/- 5 mg.m-2.min-1, p less than 0.01), were not correlated to basal glucose or insulin concentrations, and were not different from normal (lean controls: 87 +/- 4 mg.m-2.min-1; obese controls: 80 +/- 5 mg.m-2.min-1). These results suggest that the basal state in the diabetic patients is a compensated condition where glucose turnover rates are maintained near normal despite defects in insulin sensitivity.

Effects of glyburide on carbohydrate metabolism and insulin action in the liver

Increased hepatic glucose production is responsible for fasting hyperglycemia in type II diabetes. Insulin resistance is the key in this process because of the inability of inslin to suppress hepatic glucose production, thereby allowing an unopposed glucagon effect. Glyburide, one of the second-generation sulfonylureas, decreases glucose production and enhances insulin action in the liver. Available data suggest that glyburide: (1) enhances glycogen synthesis in the liver by increasing glycogen synthase; (2) inhibits glycogenolysis by decreasing phosphorylase a activity; and (3) decreases gluconeogenesis and stimulates glycolysis by decreasing A-kinase activity, which results in increased fructose 2,6-bisphosphate, one of the key regulators of carbohydrate metabolism in the liver. The effect of glyburide on the insulin-signaling mechanism(s) is distal to the insulin binding site of the alpha-subunit of the insulin receptor and the tyrosine kinase activation site of the beta-subunit.