Apres l'ingestion de glucose, l'insulino-secretion du pancreas est stimulee et la combinaison de l'hyperglycemie et de l'hyperinsulinemie doit induire la captation de glucose dans les territoires splanchique (foie et tube digestif) et peripherique (muscles) et la suppression de la production hepatique du glucose. Le but de cette conference est de prouver que, bien que la perturbation du metabolisme hepatique du glucose joue un role dans le maintien de l'etat diabetique, le foie ne joue probablement pas de role majeur dans le developpement precoce de l'hyperglycemie a jeun des DNID

Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM.

Insulin resistance in muscle and liver and β-cell failure represent the core pathophysiologic defects in type 2 diabetes. It now is recognized that the β-cell failure occurs much earlier and is more severe than previously thought. Subjects in the upper tertile of impaired glucose tolerance (IGT) are maximally/near-maximally insulin resistant and have lost over 80% of their β-cell function. In addition to the muscle, liver, and β-cell (triumvirate), the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonemia), kidney (increased glucose reabsorption), and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals. Collectively, these eight players comprise the ominous octet and dictate that: 1 ) multiple drugs used in combination will be required to correct the multiple pathophysiological defects, 2 ) treatment should be based upon reversal of known pathogenic abnormalities and not simply on reducing the A1C, and 3 ) therapy must be started early to prevent/slow the progressive β-cell failure that already is well established in IGT subjects. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which improves insulin sensitivity and has antiatherogenic effects), a thiazolidinedione (TZD) (which improves insulin sensitivity, preserves β-cell function, and exerts antiatherogenic effects), and exenatide (which preserves β-cell function and promotes weight loss). Sulfonylureas are not recommended because, after an initial improvement in glycemic control, they are associated with a progressive rise in A1C and progressive loss of β-cell function.

The natural history of type 2 diabetes has been well described in multiple populations (1–16) (rev. in (17,18). Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin (1,16,19–24). In liver, the insulin resistance is manifested by …

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From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus

Non-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.

Pathogenesis of NIDDM: A balanced overview

Nonalcoholic Steatohepatitis: Association of Insulin Resistance and Mitochondrial Abnormalities

Insulin resistance contributes to the pathophysiology of diabetes and is a hallmark of obesity, metabolic syndrome, and many cardiovascular diseases. Therefore, quantifying insulin sensitivity/resistance in humans and animal models is of great importance for epidemiological studies, clinical and basic science investigations, and eventual use in clinical practice. Direct and indirect methods of varying complexity are currently employed for these purposes. Some methods rely on steady-state analysis of glucose and insulin, whereas others rely on dynamic testing. Each of these methods has distinct advantages and limitations. Thus, optimal choice and employment of a specific method depends on the nature of the studies being performed. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. The hyperinsulinemic euglycemic glucose clamp and the insulin suppression test directly assess insulin-mediated glucose utilization under steady-state conditions that are both labor and time intensive. A slightly less complex indirect method relies on minimal model analysis of a frequently sampled intravenous glucose tolerance test. Finally, simple surrogate indexes for insulin sensitivity/resistance are available (e.g., QUICKI, HOMA, 1/insulin, Matusda index) that are derived from blood insulin and glucose concentrations under fasting conditions (steady state) or after an oral glucose load (dynamic). In particular, the quantitative insulin sensitivity check index (QUICKI) has been validated extensively against the reference standard glucose clamp method. QUICKI is a simple, robust, accurate, reproducible method that appropriately predicts changes in insulin sensitivity after therapeutic interventions as well as the onset of diabetes. In this Frontiers article, we highlight merits, limitations, and appropriate use of current in vivo measures of insulin sensitivity/resistance.

https://www.physiology.org/doi/pdf/10.1152/ajpendo.00645.2007

Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage.

The mechanism(s) and site(s) of the insulin resistance were examined in nine normal-weight noninsulin-dependent diabetic (NIDD) subjects. The euglycemic insulin clamp technique (insulin concentration approximately 100 microU/ml) was employed in combination with hepatic and femoral venous catheterization and measurement of endogenous glucose production using infusion of tritiated glucose. Total body glucose metabolism in the NIDD subjects (4.37 +/- 0.45 mg/kg per min) was 38% (P less than 0.01) lower than in controls (7.04 +/- 0.63 mg/kg per min). Quantitatively, the most important site of the insulin resistance was found to be in peripheral tissues. Leg glucose uptake in the diabetic group was reduced by 45% as compared with that in controls (6.0 +/- 0.2 vs. 11.0 +/- 0.1 mg/kg leg wt per min; P less than 0.01). A strong positive correlation was observed between leg and total body glucose uptake (r = 0.70, P less than 0.001). Assuming that muscle is the primary leg tissue responsible for glucose uptake, it could be estimated that 90 and 87% of the infused glucose was disposed of by peripheral tissues in the control and NIDD subjects, respectively. Net splanchnic glucose balance during insulin stimulation was slightly more positive in the control than in the diabetic subjects (0.31 +/- 0.10 vs. 0.05 +/- 0.19 mg/kg per min; P less than 0.07). The difference (0.26 mg/kg per min) in net splanchnic glucose balance in NIDD represented only 10% of the reduction (2.67 mg/kg per min) in total body glucose uptake in the NIDD group and thus contributed very little to the insulin resistance. The results emphasize the importance of the peripheral tissues in the disposal of infused glucose and indicate that muscle is the most important site of the insulin resistance in NIDD.

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Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus.

Cyclic somatostatin was administered intravenously (10 mug/min for 60 min) to 10 healthy overnight fasted (postabsorptive) subjects and to 5 healthy 60-h fasted subjects. In both groups, arterial insulin and glucagon fell 50% and splanchnic release of these hormones was inhibited. In the overnight fasted subjects splanchnic glucose output fell 70%, splanchnic uptake of lactate and pyruvate was unchanged, alanine uptake fell by 25%, and glycerol uptake rose more than twofold in parallel with an increase in arterial glycerol. In the 60-h fasted group splanchnic glucose output was less than 40% of that observed in the overnight fasted subjects. Somatostatin led to a further decrease (--70%) in glucose production. Splanchnic uptake of lactate and pyruvate fell by 30-40%, amino acid uptake was unchanged, while uptake of glycerol rose fivefold. Total uptake of glucose precursors thus exceeded the simultaneous glucose output by more than 200%. Splanchnic uptake of FFA rose fourfold during somatostatin while output of beta-hydroxybutyrate increased by 75%. Estimated hepatic blood flow fell 25-35% and returned to base line as soon as the somatostatin infusion ended. It is concluded that (a) somatostatin-induced hypoglucagonemia results in inhibition of splanchnic glucose output in glycogen-depleted, 60-h fasted subjects as well as in postabsorptive subjects, indicating an effect of glucagon on hepatic gluconeogenesis as well as glycogenolysis; (b) the glucagonsensitive step(s) in gluconeogenesis affected by somatostatin involves primarily intra-hepatic disposal rather than net hepatic uptake of glucose precursors; (c) splanchnic uptake of fatty acids and ketone output are increased in the face of combined insulin and glucagon deficiency; and (d) diminished splanchnic blood flow may contribute to some of the effects of somatostatin on splanchnic metabolism.

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Influence of somatostatin on splanchnic glucose metabolism in postabsorptive and 60-hour fasted humans.

Summary. The present study was undertaken to examine the role of glucagon in the regulation of hepatic glucose production during exercise. Using the hepatic vein catheter technique, the influence of somatostatin-induced hypoglucagonemia on splanchnic exchange of glucose and glucose precursors during exercise was studied in normal postabsorptive man. In the experiments hypoglucagonemia was induced 10 min before and during 40 min of supine bicycle exercise (series 1), or 1–2 h before, and during, 40 min of upright bicycle exercise (series 2). The relative work intensities were 50% (series 1) and 55% (series 2) of maximal oxygen uptake. Control studies without somatostatin were conducted in both series.

In both series, insulin and glucagon levels were suppressed by 40–50% throughout the period of somatostatin infusion. In series 1, somatostatin infusion at rest resulted in a 50 % fall in splanchnic glucose output. Onset of exercise during suppressed glucose production was followed by a rise in splanchnic glucose output similar to that seen in control subjects, but the absolute rate of glucose production was 5–25 % lower than in controls. In contrast to the euglycemia observed in the control experiment, exercise during somatostatin administration was accompanied by a 1–2 mmol/1 fall in blood glucose concentration due to the lower rate of glucose production.

In series 2, a variable glucose infusion was added to the somatostatin administration before exercise to maintain euglycemia. After 1–2 h of somatostatin administration, glucose infusion was no longer required to prevent hypoglycemia, and splanchnic glucose output had returned to the basal level. At this time exercise was started. Both the rise in splanchnic glucose production and the absolute rate of splanchnic glucose output during exercise were similar to those observed without somatostatin. However, exercise during prolonged somatostatin infusion was accompanied by a gradual 50% rise in arterial glucose concentration, whereas no change in blood glucose during exercise was seen in controls.

Influence of hypoglucagonemia on splanchnic glucose output during leg exercise in man

Summary. The aim of the present study was to investigate the influence of hepatic glycogen depletion and increased lipolysis on the response of splanchnic glucose output and ketogenesis to combined glucagon and insulin deficiency in normal man. Healthy subjects were studied after a 60-h fast and compared with a control group studied after an overnight fast, Net splanchnic exchange of glucose, gluconeogenic precursors, free fatty acids (FFA) and ketone acids were measured in the basal state and during intravenous infusion of somatostatin (9 μg/min) for 90–140 min (overnight fasted subjects) or for 5 h (60-h fasted subjects). During the infusion of somatostatin, euglycemia was maintained by a variable intravenous infusion of glucose.



Prior to somatostatin infusion, after an overnight (12–14 h) fast, splanchnic uptake of glucose precursors (alanine, lactate, pyruvate, glycerol) could account for 26% of splanchnic glucose output (SGO) indicating primarily glycogenolysis. Somatostatin infusion resulted in a 50% reduction in both insulin and glucagon concentrations and a transient decline in SGO which returned to baseline values by 86±ll min at which point the glucose infusion was no longer necessary to maintain euglycemia. Arterial concentrations of FFA and β-OH-butyrate and splanchnic β-OH-butyrate production rose 2.5-fold, 6-fold and 7.5-fold, respectively, in response to somatostatin infusion.



In the 60-h fasted state, basal SGO (0.29±0.03 mmoymin) was 60% lower than after an overnight fast and basal splanchnic uptake of glucose precursors could account for 85% of SGO, indicating primarily gluconeogenesis. Somatostatin administration suppressed the arterial glucagon and insulin concentrations to values comparable to those observed during the infusion in the overnight fasted state. SGO fell promptly in response to the somatostatin infusion and in contrast to the overnight fasted state, remained inhibited by 50–100% for 5 h. Infusion of glucose was consequently necessary to maintain euglycemia throughout the 5-h infusion of somatostatin. Splanchnic uptake of gluconeogenic precursors was unchanged during somatostatin despite the sustained suppression of SGO. Basal arterial concentration and splanchnic exchange of β-OH-butyrate were respectively 22-fold and 6- to 7-fold elevated and basal FFA concentration was 70% increased as compared to the corresponding values in the overnight fasted state. Somatostatin infusion resulted in a rise in arterial FFA concentration (25–50% in all subjects) while the arterial concentrations and splanchnic release of ketone acids (acetoacetate +β-OH-butyrate) showed a variable response, rising in three subjects and declining in two. Nevertheless, splanchnic ketone acid production in the basal state and during the somatostatin infusion correlated directly with splanchnic inflow of FFA (arterial FFA concentration × hepatic plasma flow). The variable responses in ketogenesis could thus be ascribed to variable reductions in splanchnic blood flow induced by somatostatin and as a consequence, its varying effects on splanchnic inflow of FFA.



These data thus demonstrate that combined hypoglucagonemia and hypoinsulinemia induced in humans by somatostatin (a) causes a persistent rather than transient inhibition of splanchnic glucose output when liver glycogen stores have been depleted by 60-h fasting and hepatic glucose production is dependent primarily on gluconeogenesis; and (b) fails to interfere with hepatic ketogenesis so long as FFA delivery to the splanchnic bed is maintained. These findings indicate that in the face of insulin deficiency, basal glucagon levels may not be necessary to maintain hepatic glycogenolysis or ketogenesis but may be essential to maintain gluconeogenesis.

Ola Björkman

Papers

Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus.

Influence of somatostatin on splanchnic glucose metabolism in postabsorptive and 60-hour fasted humans.

Influence of hypoglucagonemia on splanchnic glucose output during leg exercise in man

Role of basal glucagon levels in the regulation of splanchnic glucose output and ketogenesis in insulin-deficient humans.