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Sahoo B, Srivastava M, Katiyar A, Ecelbarger C, Tiwari S. Liver or kidney: Who has the oar in the gluconeogenesis boat and when? World J Diabetes 2023; 14:1049-1056. [PMID: 37547592 PMCID: PMC10401452 DOI: 10.4239/wjd.v14.i7.1049] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/20/2023] [Accepted: 04/11/2023] [Indexed: 07/12/2023] Open
Abstract
Gluconeogenesis is an endogenous process of glucose production from non-carbohydrate carbon substrates. Both the liver and kidneys express the key enzymes necessary for endogenous glucose production and its export into circulation. We would be remiss to add that more recently gluconeogenesis has been described in the small intestine, especially under high-protein, low-carbohydrate diets. The contribution of the liver glucose release, the net glucose flux, towards systemic glucose is already well known. The liver is, in most instances, the primary bulk contributor due to the sheer size of the organ (on average, over 1 kg). The contribution of the kidney (at just over 100 g each) to endogenous glucose production is often under-appreciated, especially on a weight basis. Glucose is released from the liver through the process of glycogenolysis and gluconeogenesis. Renal glucose release is almost exclusively due to gluconeogenesis, which occurs in only a fraction of the cells in that organ (proximal tubule cells). Thus, the efficiency of glucose production from other carbon sources may be superior in the kidney relative to the liver or at least on the level. In both these tissues, gluconeogenesis regulation is under tight hormonal control and depends on the availability of substrates. Liver and renal gluconeogenesis are differentially regulated under various pathological conditions. The impact of one source vs the other changes, based on post-prandial state, acid-base balance, hormonal status, and other less understood factors. Which organ has the oar (is more influential) in driving systemic glucose homeostasis is still in-conclusive and likely changes with the daily rhythms of life. We reviewed the literature on the differences in gluconeogenesis regulation between the kidneys and the liver to gain an insight into who drives the systemic glucose levels under various physiological and pathological conditions.
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Affiliation(s)
- Biswajit Sahoo
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Medha Srivastava
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Arpit Katiyar
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Carolyn Ecelbarger
- Department of Medicine, Georgetown University, Washington, DC 20057, United States
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Koh HCE, Cao C, Mittendorfer B. Insulin Clearance in Obesity and Type 2 Diabetes. Int J Mol Sci 2022; 23:596. [PMID: 35054781 PMCID: PMC8776220 DOI: 10.3390/ijms23020596] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/02/2022] [Accepted: 01/03/2022] [Indexed: 02/06/2023] Open
Abstract
Plasma insulin clearance is an important determinant of plasma insulin concentration. In this review, we provide an overview of the factors that regulate insulin removal from plasma and discuss the interrelationships among plasma insulin clearance, excess adiposity, insulin sensitivity, and type 2 diabetes (T2D). We conclude with the perspective that the commonly observed lower insulin clearance rate in people with obesity, compared with lean people, is not a compensatory response to insulin resistance but occurs because insulin sensitivity and insulin clearance are mechanistically, directly linked. Furthermore, insulin clearance decreases postprandially because of the marked increase in insulin delivery to tissues that clear insulin. The commonly observed high postprandial insulin clearance in people with obesity and T2D likely results from the relatively low insulin secretion rate, not an impaired adaptation of tissues that clear insulin.
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Affiliation(s)
| | | | - Bettina Mittendorfer
- Center for Human Nutrition, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8031-14-0002, St. Louis, MO 63110, USA; (H.-C.E.K.); (C.C.)
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Sharma R, Tiwari S. Renal gluconeogenesis in insulin resistance: A culprit for hyperglycemia in diabetes. World J Diabetes 2021; 12:556-568. [PMID: 33995844 PMCID: PMC8107972 DOI: 10.4239/wjd.v12.i5.556] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/27/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Renal gluconeogenesis is one of the major pathways for endogenous glucose production. Impairment in this process may contribute to hyperglycemia in cases with insulin resistance and diabetes. We reviewed pertinent studies to elucidate the role of renal gluconeogenesis regulation in insulin resistance and diabetes. A consensus on the suppressive effect of insulin on kidney gluconeogenesis has started to build up. Insulin-resistant models exhibit reduced insulin receptor (IR) expression and/or post-receptor signaling in their kidney tissue. Reduced IR expression or post-receptor signaling can cause impairment in insulin’s action on kidneys, which may increase renal gluconeogenesis in the state of insulin resistance. It is now established that the kidney contributes up to 20% of all glucose production via gluconeogenesis in the post-absorptive phase. However, the rate of renal glucose release excessively increases in diabetes. The rise in renal glucose release in diabetes may contribute to fasting hyperglycemia and increased postprandial glucose levels. Enhanced glucose release by the kidneys and renal expression of the gluconeogenic-enzyme in diabetic rodents and humans further point towards the significance of renal gluconeogenesis. Overall, the available literature suggests that impairment in renal gluconeogenesis in an insulin-resistant state may contribute to hyperglycemia in type 2 diabetes.
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Affiliation(s)
- Rajni Sharma
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Swasti Tiwari
- Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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Koshimizu TA, Nakamura K, Egashira N, Hiroyama M, Nonoguchi H, Tanoue A. Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems. Physiol Rev 2012; 92:1813-64. [DOI: 10.1152/physrev.00035.2011] [Citation(s) in RCA: 250] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The neurohypophysial hormone arginine vasopressin (AVP) is essential for a wide range of physiological functions, including water reabsorption, cardiovascular homeostasis, hormone secretion, and social behavior. These and other actions of AVP are mediated by at least three distinct receptor subtypes: V1a, V1b, and V2. Although the antidiuretic action of AVP and V2 receptor in renal distal tubules and collecting ducts is relatively well understood, recent years have seen an increasing understanding of the physiological roles of V1a and V1b receptors. The V1a receptor is originally found in the vascular smooth muscle and the V1b receptor in the anterior pituitary. Deletion of V1a or V1b receptor genes in mice revealed that the contributions of these receptors extend far beyond cardiovascular or hormone-secreting functions. Together with extensively developed pharmacological tools, genetically altered rodent models have advanced the understanding of a variety of AVP systems. Our report reviews the findings in this important field by covering a wide range of research, from the molecular physiology of V1a and V1b receptors to studies on whole animals, including gene knockout/knockdown studies.
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Affiliation(s)
- Taka-aki Koshimizu
- Department of Pharmacology, Division of Molecular Pharmacology, Jichi Medical University, Tochigi, Japan; Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan; and Department of Internal Medicine, Kitasato University, Kitasato Institute Medical Center Hospital, Saitama, Japan
| | - Kazuaki Nakamura
- Department of Pharmacology, Division of Molecular Pharmacology, Jichi Medical University, Tochigi, Japan; Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan; and Department of Internal Medicine, Kitasato University, Kitasato Institute Medical Center Hospital, Saitama, Japan
| | - Nobuaki Egashira
- Department of Pharmacology, Division of Molecular Pharmacology, Jichi Medical University, Tochigi, Japan; Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan; and Department of Internal Medicine, Kitasato University, Kitasato Institute Medical Center Hospital, Saitama, Japan
| | - Masami Hiroyama
- Department of Pharmacology, Division of Molecular Pharmacology, Jichi Medical University, Tochigi, Japan; Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan; and Department of Internal Medicine, Kitasato University, Kitasato Institute Medical Center Hospital, Saitama, Japan
| | - Hiroshi Nonoguchi
- Department of Pharmacology, Division of Molecular Pharmacology, Jichi Medical University, Tochigi, Japan; Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan; and Department of Internal Medicine, Kitasato University, Kitasato Institute Medical Center Hospital, Saitama, Japan
| | - Akito Tanoue
- Department of Pharmacology, Division of Molecular Pharmacology, Jichi Medical University, Tochigi, Japan; Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan; and Department of Internal Medicine, Kitasato University, Kitasato Institute Medical Center Hospital, Saitama, Japan
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Abstract
According to current textbook wisdom the liver is the exclusive site of glucose production in humans in the postabsorptive state. Although animal and in vitro studies have documented that the kidney is capable of gluconeogenesis, glucose production by the human kidney has been regarded as negligible. This knowledge is based on net balance measurements across the kidney. Recent studies combining isotopic and balance techniques have demonstrated that the human kidney is involved in the regulation of glucose homeostasis by making glucose via gluconeogenesis, taking up glucose from the circulation, and by reabsorbing glucose from the glomerular filtrate. The human liver and kidneys release approximately equal amounts of glucose via gluconeogenesis in the postabsorptive state. In the postprandial state, although overall endogenous glucose release decreases substantially, renal gluconeogenesis actually increases by approximately 2-fold. Following meal ingestion, glucose utilization by the kidney increases. Increased glucose uptake into the kidney may be implicated in diabetic nephropathy. Normally each day, ∼ 180 g of glucose is filtered by the kidneys; almost all of this is reabsorbed by means of sodium glucose cotransporter 2 (SGLT2), expressed in the proximal tubules. However, the capacity of SGLT2 to reabsorb glucose from the renal tubules is finite and when plasma glucose concentrations exceed a threshold, glucose begins to appear in the urine. Renal glucose release is stimulated by epinephrine and is inhibited by insulin. Handling of glucose by the kidney is altered in type 2 diabetes mellitus (T2DM): renal gluconeogenesis and renal glucose uptake are increased in both the postabsorptive and postprandial states, and renal glucose reabsorption is also increased Since renal glucose release is almost exclusively due to gluconeogenesis, it seems that the kidney is as important gluconeogenic organ as the liver. The most important renal gluconeogenic precursors appear to be lactae glutamine and glycerol.
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Affiliation(s)
- Asimina Mitrakou
- Department of Clinical Therapeutics, Athens University Medical School, Athens, Greece.
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Enhanced expressions of arginine vasopressin (Avp) in the hypothalamic paraventricular and supraoptic nuclei of type 2 diabetic rats. Neurochem Res 2007; 33:833-41. [PMID: 17940875 DOI: 10.1007/s11064-007-9519-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2007] [Accepted: 09/25/2007] [Indexed: 01/16/2023]
Abstract
Arginine vasopressin (AVP) is known to a neuropeptide that plays important roles in water conservation, sodium homeostasis, and in the regulation of serum osmolality. Several studies have reported that the elevated AVP level is related with diabetes mellitus as an acute or chronic stressor using type 1 diabetes mellitus animal models. However, it is unclear as to how the immunoreactivity and protein level of AVP in the brain is regulated in animal models of type 2 diabetes mellitus. In the present study, Zucker diabetic fatty (ZDF) rats were employed as a type 2 diabetes mellitus model and were compared with Zucker lean control (ZLC) rats with respect to AVP protein expression. Furthermore, in order to verify the regulation of AVP expression before and after the onset of diabetes mellitus, pre-diabetic rats (4 week-old) and obese-diabetic rats (12 week-old) were used. Blood glucose levels and water consumption were also measured and the results showed significantly high in 12 week-old ZDF than any other groups. AVP expression levels in the paraventricular nucleus and supraoptic nucleus were found to be significantly higher in 12 week-old ZDF rats than in 12 week-old ZLC rats and than in 4 week-old rats by immunostaining and western blotting. Enhanced expression of AVP in these animals may be associated with type 2 diabetes mellitus.
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Aoyagi T, Birumachi JI, Hiroyama M, Fujiwara Y, Sanbe A, Yamauchi J, Tanoue A. Alteration of glucose homeostasis in V1a vasopressin receptor-deficient mice. Endocrinology 2007; 148:2075-84. [PMID: 17303660 DOI: 10.1210/en.2006-1315] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Arginine-vasopressin (AVP) is known to be involved in maintaining glucose homeostasis, and AVP-resistance is observed in poorly controlled non-insulin-dependent diabetes mellitus subjects, resulting in a lowered plasma volume. Recently we reported that V1a vasopressin receptor-deficient (V1aR(-/-)) mice exhibited a decreased circulating blood volume and hypermetabolism of fat accompanied with impaired insulin-signaling. Here we further investigated the roles of the AVP/V1a receptor in regulating glucose homeostasis and plasma volume using V1aR(-/-) mice. The plasma glucose levels at the baseline or during a glucose tolerance test were higher in V1aR(-/-) than wild-type (WT) mice. Moreover, a hyperinsulinemic-euglycemic clamp revealed that the glucose infusion rate was significantly lower in V1aR(-/-) mice than in WT mice and that hepatic glucose production was higher in V1aR(-/-) mice than WT mice. In contrast to the increased hepatic glucose production, the liver glycogen content was decreased in the mutant mice. These results indicated that the mutant mice had impaired glucose tolerance. Furthermore, feeding V1aR(-/-) mice a high-fat diet accompanied by increased calorie intake resulted in significantly overt obesity in comparison with WT mice. In addition, we found that the circulating plasma volume and aldosterone level were decreased in V1aR(-/-) mice, although the plasma AVP level was increased. These results suggested that the effect of AVP on water recruitment was disturbed in V1aR(-/-) mice. Thus, we demonstrated that one of the AVP-resistance conditions resulting from deficiency of the V1a receptor leads to decreased plasma volume as well as impaired glucose homeostasis, which can progress to obesity under conditions of increased calorie intake.
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Affiliation(s)
- Toshinori Aoyagi
- Department of Pharmacology, National Research Institute for Child Health and Development, 2-10-1, Okura, Setagaya-ku, Tokyo 157-8535, Japan
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Abstract
Type 2 diabetes is characterized by insulin resistance and impaired insulin secretion. Considerable evidence implicates altered fat topography and defects in adipocyte metabolism in the pathogenesis of type 2 diabetes. In individuals who develop type 2 diabetes, fat cells tend to be enlarged. Enlarged fat cells are resistant to the antilipolytic effects of insulin, leading to day-long elevated plasma free fatty acid (FFA) levels. Chronically increased plasma FFA stimulates gluconeogenesis, induces hepatic and muscle insulin resistance, and impairs insulin secretion in genetically predisposed individuals. These FFA-induced disturbances are referred to as lipotoxicity. Enlarged fat cells also have diminished capacity to store fat. When adipocyte storage capacity is exceeded, lipid 'overflows' into muscle and liver, and possibly the beta-cells of the pancreas, exacerbating insulin resistance and further impairing insulin secretion. In addition, dysfunctional fat cells produce excessive amounts of insulin resistance-inducing, inflammatory and atherosclerosis-provoking cytokines, and fail to secrete normal amounts of insulin-sensitizing cytokines. As more evidence emerges, there is a stronger case for targeting adipose tissue in the treatment of type 2 diabetes. Peroxisome-proliferator activated receptor gamma (PPARgamma) agonists, for example the thiazolidinediones, redistribute fat within the body (decrease visceral and hepatic fat; increase subcutaneous fat) and have been shown to enhance adipocyte insulin sensitivity, inhibit lipolysis, reduce plasma FFA and favourably influence the production of adipocytokines. This article examines in detail the role of adipose tissue in the pathogenesis of type 2 diabetes and highlights the potential of PPAR agonists to improve the management of patients with the condition.
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Affiliation(s)
- R A DeFronzo
- Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA.
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Krssak M, Brehm A, Bernroider E, Anderwald C, Nowotny P, Dalla Man C, Cobelli C, Cline GW, Shulman GI, Waldhäusl W, Roden M. Alterations in postprandial hepatic glycogen metabolism in type 2 diabetes. Diabetes 2004; 53:3048-56. [PMID: 15561933 DOI: 10.2337/diabetes.53.12.3048] [Citation(s) in RCA: 228] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Decreased skeletal muscle glucose disposal and increased endogenous glucose production (EGP) contribute to postprandial hyperglycemia in type 2 diabetes, but the contribution of hepatic glycogen metabolism remains uncertain. Hepatic glycogen metabolism and EGP were monitored in type 2 diabetic patients and nondiabetic volunteer control subjects (CON) after mixed meal ingestion and during hyperglycemic-hyperinsulinemic-somatostatin clamps applying 13C nuclear magnetic resonance spectroscopy (NMRS) and variable infusion dual-tracer technique. Hepatocellular lipid (HCL) content was quantified by 1H NMRS. Before dinner, hepatic glycogen was lower in type 2 diabetic patients (227 +/- 6 vs. CON: 275 +/- 10 mmol/l liver, P < 0.001). After meal ingestion, net synthetic rates were 0.76 +/- 0.16 (type 2 diabetic patients) and 1.36 +/- 0.15 mg x kg(-1) x min(-1) (CON, P < 0.02), resulting in peak concentrations of 283 +/- 15 and 360 +/- 11 mmol/l liver. Postprandial rates of EGP were approximately 0.3 mg x kg(-1) x min(-1) (30-170 min; P < 0.05 vs. CON) higher in type 2 diabetic patients. Under clamp conditions, type 2 diabetic patients featured approximately 54% lower (P < 0.03) net hepatic glycogen synthesis and approximately 0.5 mg x kg(-1) x min(-1) higher (P < 0.02) EGP. Hepatic glucose storage negatively correlated with HCL content (R = -0.602, P < 0.05). Type 2 diabetic patients exhibit 1) reduction of postprandial hepatic glycogen synthesis, 2) temporarily impaired suppression of EGP, and 3) no normalization of these defects by controlled hyperglycemic hyperinsulinemia. Thus, impaired insulin sensitivity and/or chronic glucolipotoxicity in addition to the effects of an altered insulin-to-glucagon ratio or increased free fatty acids accounts for defective hepatic glycogen metabolism in type 2 diabetic patients.
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Affiliation(s)
- Martin Krssak
- Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
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Abstract
This article provides an overview of the pathogenesis of type 2 diabetes mellitus. Discussion begins by describing normal glucose homeostasis and ingestion of a typical meal and then discusses glucose homeostasis in diabetes. Topics covered include insulin secretion in type 2 diabetes mellitus and insulin resistance, the site of insulin resistance, the interaction between insulin sensitivity and secretion, the role of adipocytes in the pathogenesis of type 2 diabetes, cellular mechanisms of insulin resistance including glucose transport and phosphorylation, glycogen and synthesis,glucose and oxidation, glycolysis, and insulin signaling.
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Affiliation(s)
- Ralph A DeFronzo
- Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA
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Connolly CC, Aglione LN, Smith MS, Lacy DB, Moore MC. Insulin action during late pregnancy in the conscious dog. Am J Physiol Endocrinol Metab 2004; 286:E909-15. [PMID: 14749203 DOI: 10.1152/ajpendo.00143.2003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Our aim was to assess the magnitude of peripheral insulin resistance and whether changes in hepatic insulin action were evident in a canine model of late (3rd trimester) pregnancy. A 3-h hyperinsulinemic (5 mU.kg(-1).min(-1)) euglycemic clamp was conducted using conscious, 18-h-fasted pregnant (P; n = 6) and nonpregnant (NP; n = 6) female dogs in which catheters for intraportal insulin infusion and assessment of hepatic substrate balances were implanted approximately 17 days before experimentation. Arterial plasma insulin rose from 11 +/- 2 to 192 +/- 24 and 4 +/- 2 to 178 +/- 5 microU/ml in the 3rd h in NP and P, respectively. Glucagon fell equivalently in both groups. Basal net hepatic glucose output was lower in NP (1.9 +/- 0.1 vs. 2.4 +/- 0.2 mg.kg(-1).min(-1), P < 0.05). Hyperinsulinemia completely suppressed hepatic glucose release in both groups (-0.4 +/- 0.2 and -0.1 +/- 0.2 mg.kg(-1).min(-1) in NP and P, respectively). More exogenous glucose was required to maintain euglycemia in NP (15.2 +/- 1.3 vs. 11.5 +/- 1.1 mg.kg(-1).min(-1), P < 0.05). Nonesterified fatty acids fell similarly in both groups. Net hepatic gluconeogenic amino acid uptake with high insulin did not differ in NP and P. Peripheral insulin action is markedly impaired in this canine model of pregnancy, whereas hepatic glucose production is completely suppressed by high circulating insulin levels.
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Affiliation(s)
- Cynthia C Connolly
- Department of Molecular Physiology and Biophysics, Diabetes Research and Training Center, Vanderbilt University School of Medicine, Nashville, TN 37232-0615, USA
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Affiliation(s)
- Peter Staehr
- Department of Endocrinology M, Odense University Hospital, DK-5000, Odense C, Denmark.
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Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 2004; 89:463-78. [PMID: 14764748 DOI: 10.1210/jc.2003-030723] [Citation(s) in RCA: 444] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Harold Bays
- Diabetes Division, University of Texas Health Science Center, San Antonio, Texas 78229, USA
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Stulnig TM, Waldhäusl W. 11beta-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes. Diabetologia 2004; 47:1-11. [PMID: 14652720 DOI: 10.1007/s00125-003-1284-4] [Citation(s) in RCA: 77] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2003] [Revised: 10/29/2003] [Indexed: 10/26/2022]
Abstract
Obesity and Type 2 diabetes mellitus are associated with abnormal regulation of glucocorticoid metabolism that are highlighted by clinical similarities between the sequelae of insulin resistance and Cushing's syndrome, as well as glucocorticoids' functional antagonism to insulin. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activates functionally inert glucocorticoid precursors (cortisone) to active glucocorticoids (cortisol) within insulin target tissues, such as adipose tissue, thereby regulating local glucocorticoid action. Recent data, mainly from rodents, provide considerable evidence for a causal role of 11beta-HSD1 for the development of visceral obesity and Type 2 diabetes though data in humans are not unequivocal. This review summarizes current evidence on a possible role of 11beta-HSD1 for development of the metabolic syndrome, raising the possibility of novel therapeutic options for the treatment of Type 2 diabetes by inhibition or down-regulation of 11beta-HSD1 activity.
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Affiliation(s)
- T M Stulnig
- Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
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Abstract
The liver is mainly responsible for maintaining normal concentrations of blood glucose by its ability to store glucose as glycogen and to produce glucose from glycogen breakdown or gluconeogenic precursors. During the last decade, new techniques have made it possible to gain further insight into the turnover of hepatic glucose and glycogen in humans. Hepatic glycogen varies from approximately 200 to approximately 450 mM between overnight fasted and postprandial conditions. Patients with type-1 diabetes (T1DM), type 2 diabetes (T2DM) or partial agenesis of the pancreas exhibit increased endogenous glucose production and synthesize only 25-45% of hepatic glycogen compared with non-diabetic humans. This defect can be partly restored in T1DM by combined long- and short-term optimized treatment with insulin. In T2DM, increased gluconeogenesis was identified as the main cause of elevated glucose production and fasting hyperglycaemia. These patients also exhibit augmented intracellular lipid accumulation which could hint at a link between deranged glucose and lipid metabolism in insulin-resistant states.
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Affiliation(s)
- Michael Roden
- Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna Medical School, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
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Affiliation(s)
- Mandeep Bajaj
- Diabetes Division, Department od Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78284-7886, USA.
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Stingl H, Schnedl WJ, Krssak M, Bernroider E, Bischof MG, Lahousen T, Pacini G, Roden M. Reduction of hepatic glycogen synthesis and breakdown in patients with agenesis of the dorsal pancreas. J Clin Endocrinol Metab 2002; 87:4678-85. [PMID: 12364458 DOI: 10.1210/jc.2002-020036] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
In a family with agenesis of the dorsal pancreas only the mother presents with insulin-dependent diabetes mellitus, whereas her sons are glucose tolerant. We examined whether metabolic defects can be detected early in this disease. Plasma glucose profiles were obtained from patients with dorsal pancreas agenesis and from matched healthy subjects. Hepatic glycogen synthesis and breakdown were determined from the time course of glycogen concentrations using noninvasive (13)C nuclear magnetic resonance spectroscopy. Gluconeogenesis was calculated from the difference between glucose production (measured with D-[6,6-(2)H(2)]glucose) and glycogen breakdown. Frequently sampled iv glucose tolerance tests were performed to assess insulin secretion and sensitivity. The mean plasma glucose level was higher (12.9 +/- 0.4 vs. 5.9 +/- 0.1 mmol/liter), whereas the peak plasma insulin level was lower (236 vs. 397 +/- 23 pmol/liter) in the diabetic mother than in her nondiabetic sons and healthy subjects. In all patients, however, glycogen synthesis and breakdown were reduced by approximately 55% (P < 0.05) and 40% (P < 0.02), respectively. Gluconeogenesis (6.8 +/- 0.8 vs. 4.2 +/- 0.3 micro mol/kg.min; P < 0.05) and hepatic insulin clearance (6.8 +/- 1.3 vs. 2.8 +/- 1.0 ml/kg.min) were increased in all patients. In conclusion, patients with complete agenesis of the dorsal pancreas exhibit marked defects in hepatic glycogen metabolism, which are present even in the nondiabetic offspring.
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Affiliation(s)
- Harald Stingl
- Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna, A-1090 Vienna, Austria
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Staehr P, Hother-Nielsen O, Beck-Nielsen H. Hepatic glucose production: therapeutic target in type 2 diabetes? Diabetes Obes Metab 2002; 4:215-23. [PMID: 12099970 DOI: 10.1046/j.1463-1326.2002.00177.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Affiliation(s)
- P Staehr
- Diabetes Research Centre, Odense University Hospital, Denmark
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Abstract
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.
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Affiliation(s)
- Christian Meyer
- Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Avenue, Box MED/CRC, Rochester, NY 14642, USA
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Aoki TT, Grecu EO, Arcangeli MA, Benbarka MM, Prescott P, Ahn JH. Chronic intermittent intravenous insulin therapy: a new frontier in diabetes therapy. Diabetes Technol Ther 2001; 3:111-23. [PMID: 11469701 DOI: 10.1089/152091501750220073] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The limited success achieved in controlling diabetes and its complications with conventional insulin therapy suggests the need for reevaluation of the appropriateness of insulin administration protocols. Indeed, conventional subcutaneous insulin administration produces slowly changing blood insulin levels and suboptimal hepatocyte insulinization resulting in impaired hepatic capacity for processing incoming dietary glucose. The novel approach to insulin administration known as chronic intermittent intravenous insulin therapy (CIIIT) delivers insulin in a pulsatile fashion and achieves physiological insulin concentration in the portal vein. Done as a weekly outpatient procedure combined with daily intensive subcutaneous insulin therapy, this procedure has been shown to (1) significantly improve glycemic control while decreasing the incidence of hypoglycemic events, (2) improve hypertension control, (3) slow the progression of overt diabetic nephropathy, and (4) reverse some manifestations of diabetic autonomic neuropathy (e.g., abnormal circadian blood pressure pattern, severe postural hypotension, and hypoglycemia unawareness).
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Affiliation(s)
- T T Aoki
- Division of Endocrinology, University of California, Davis, Sacramento 95817, USA.
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22
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The effects of free fatty acids on glucose transport and phosphorylation in human skeletal muscle. ACTA ACUST UNITED AC 2000. [DOI: 10.1097/00060793-200008000-00006] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Roche E, Maestre I, Martín F, Fuentes E, Casero J, Reig JA, Soria B. Nutrient toxicity in pancreatic beta-cell dysfunction. J Physiol Biochem 2000; 56:119-28. [PMID: 11014617 DOI: 10.1007/bf03179907] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Nutrients, such as glucose and fatty acids, have a dual effect on pancreatic beta-cell function. Acute administration of high glucose concentrations to pancreatic beta-cells stimulates insulin secretion. In addition, short term exposure of this cell type to dietary fatty acids potentiates glucose-induced insulin release. On the other hand, long-term exposure to these nutrients causes impaired insulin secretion, characterized by elevated exocytosis at low concentrations of glucose and no response when glucose increases in the extracellular medium. In addition, other phenotypic changes are observed in these conditions. One major step in linking these phenotypic changes to the diabetic pathology has been the recognition of both glucose and fatty acids as key modulators of beta-cell gene expression. This could explain the adaptative response of the cell to sustained nutrient concentration. Once this phase is exhausted, the beta-cell becomes progressively unresponsive to glucose and this alteration is accompanied by the irreversible induction of apoptotic programs. The aim of this review is to present actual data concerning the development of the toxicity to the main nutrients glucose and fatty acids in the pancreatic beta-cell and to find a possible link to the development of type 2 diabetes.
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Affiliation(s)
- E Roche
- Instituto de Bioingeniería, Universidad Miguel Hernández, San Juan, Alicante, Spain
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Abstract
Recent studies have shown that increased hepatic gluconeogenesis is the predominant contributor to fasting hyperglycemia - the hallmark of type 2 diabetes. Although it has been known for a long time that over-supply of fat is able to stimulate gluconeogenesis both in-vitro and in-vivo, neither the leading substrate nor the mechanism responsible for this phenomenon have been fully identified. Recent observations that the glyoxylate pathway may exist in animals has shed light on this question. The glyoxylate pathway is able to convert fatty acid into glucose but has been thought to be absent in animals. Although further evidence is needed, current available data does suggest a possible mechanism which, by integrating both glucose and lipid metabolism together rather than interpreting them separately, may explain the role of fatty acids in hepatic insulin resistance. This hypothesis is based on current understanding of insulin resistance and supported by many laboratory observations.
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Affiliation(s)
- S Song
- Department of Medicine, University of Melbourne, Australia
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Siler SQ, Neese RA, Christiansen MP, Hellerstein MK. The inhibition of gluconeogenesis following alcohol in humans. THE AMERICAN JOURNAL OF PHYSIOLOGY 1998; 275:E897-907. [PMID: 9815011 DOI: 10.1152/ajpendo.1998.275.5.e897] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Accurate quantification of gluconeogenic flux following alcohol ingestion in overnight-fasted humans has yet to be reported. [2-13C1]glycerol, [U-13C6]glucose, [1-2H1]galactose, and acetaminophen were infused in normal men before and after the consumption of 48 g alcohol or a placebo to quantify gluconeogenesis, glycogenolysis, hepatic glucose production, and intrahepatic gluconeogenic precursor availability. Gluconeogenesis decreased 45% vs. the placebo (0.56 +/- 0.05 to 0.44 +/- 0.04 mg. kg-1. min-1 vs. 0.44 +/- 0.05 to 0.63 +/- 0.09 mg. kg-1. min-1, respectively, P < 0. 05) in the 5 h after alcohol ingestion, and total gluconeogenic flux was lower after alcohol compared with placebo. Glycogenolysis fell over time after both the alcohol and placebo cocktails, from 1.46-1. 47 mg. kg-1. min-1 to 1.35 +/- 0.17 mg. kg-1. min-1 (alcohol) and 1. 26 +/- 0.20 mg. kg-1. min-1, respectively (placebo, P < 0.05 vs. baseline). Hepatic glucose output decreased 12% after alcohol consumption, from 2.03 +/- 0.21 to 1.79 +/- 0.21 mg. kg-1. min-1 (P < 0.05 vs. baseline), but did not change following the placebo. Estimated intrahepatic gluconeogenic precursor availability decreased 61% following alcohol consumption (P < 0.05 vs. baseline) but was unchanged after the placebo (P < 0.05 between treatments). We conclude from these results that gluconeogenesis is inhibited after alcohol consumption in overnight-fasted men, with a somewhat larger decrease in availability of gluconeogenic precursors but a smaller effect on glucose production and no effect on plasma glucose concentrations. Thus inhibition of flux into the gluconeogenic precursor pool is compensated by changes in glycogenolysis, the fate of triose-phosphates, and peripheral tissue utilization of plasma glucose.
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Affiliation(s)
- S Q Siler
- Department of Nutritional Sciences, University of California, Berkeley CA 94720-3104, USA
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Meyer C, Stumvoll M, Nadkarni V, Dostou J, Mitrakou A, Gerich J. Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus. J Clin Invest 1998; 102:619-24. [PMID: 9691098 PMCID: PMC508922 DOI: 10.1172/jci2415] [Citation(s) in RCA: 214] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Release of glucose by liver and kidney are both increased in diabetic animals. Although the overall release of glucose into the circulation is increased in humans with diabetes, excessive release of glucose by either their liver or kidney has not as yet been demonstrated. The present experiments were therefore undertaken to assess the relative contributions of hepatic and renal glucose release to the excessive glucose release found in type 2 diabetes. Using a combination of isotopic and balance techniques to determine total systemic glucose release and renal glucose release in postabsorptive type 2 diabetic subjects and age-weight-matched nondiabetic volunteers, their hepatic glucose release was then calculated as the difference between total systemic glucose release and renal glucose release. Renal glucose release was increased nearly 300% in diabetic subjects (321+/-36 vs. 125+/-15 micromol/min, P < 0.001). Hepatic glucose release was increased approximately 30% (P = 0.03), but increments in hepatic and renal glucose release were comparable (2.60+/-0.70 vs. 2.21+/-0.32, micromol.kg-1.min-1, respectively, P = 0.26). Renal glucose uptake was markedly increased in diabetic subjects (353+/-48 vs. 103+/-10 micromol/min, P < 0.001), resulting in net renal glucose uptake in the diabetic subjects (92+/-50 micromol/ min) versus a net output in the nondiabetic subjects (21+/-14 micromol/min, P = 0.043). Renal glucose uptake was inversely correlated with renal FFA uptake (r = -0.51, P < 0.01), which was reduced by approximately 60% in diabetic subjects (10. 9+/-2.7 vs. 27.0+/-3.3 micromol/min, P < 0.002). We conclude that in type 2 diabetes, both liver and kidney contribute to glucose overproduction and that renal glucose uptake is markedly increased. The latter may suppress renal FFA uptake via a glucose-fatty acid cycle and explain the accumulation of glycogen commonly found in the diabetic kidney.
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Affiliation(s)
- C Meyer
- Departments of Medicine and Physiology and Pharmacology, University of Rochester School of Medicine, Rochester, New York 14642, USA
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Boden G, Chen X. Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. J Clin Invest 1995; 96:1261-8. [PMID: 7657800 PMCID: PMC185747 DOI: 10.1172/jci118160] [Citation(s) in RCA: 247] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
It was the aim of this study to determine whether FFA inhibit insulin-stimulated whole body glucose uptake and utilization in patients with non-insulin-dependent diabetes. We performed five types of isoglycemic (approximately 11mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin; (c) with insulin plus glycerol; (d) with saline; (e) with saline plus fat/heparin and two types of euglycemic (approximately 5mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin. During these studies, we determined rates of glucose uptake, glycolysis (both with 3[3H] glucose), glycogen synthesis (determined as glucose uptake minus glycolysis), carbohydrate oxidation (by indirect calorimetry) and nonoxidative glycolysis (determined as glycolysis minus carbohydrate oxidation). Fat/heparin infusion did not affect basal glucose uptake, but inhibited total stimulated (insulin stimulated plus basal) glucose uptake by 40-50% in isoglycemic and in euglycemic patients at plasma FFA concentration of approximately 950 and approximately 550 microM, respectively. In isoglycemic patients, the 40-50% inhibition of total stimulated glucose uptake was due to near complete inhibition of the insulin-stimulated part of glucose uptake. Proportional inhibition of glucose uptake, glycogen synthesis, and glycolysis suggested a major FFA-mediated defect involving glucose transport and/or phosphorylation. In summary, fat produced proportional inhibitions of insulin-stimulated glucose uptake and of intracellular glucose utilization. We conclude, that physiologically elevated levels of FFa could potentially be responsible for a large part of the peripheral insulin resistance in patients with non-insulin-dependent diabetes mellitus.
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Affiliation(s)
- G Boden
- Division of Endocrinology/Metabolism, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA
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Fasching P, Ratheiser K, Nowotny P, Uurzemann S, Parzer S, Waldhäusl W. Insulin production following intravenous glucose, arginine, and valine: different pattern in patients with impaired glucose tolerance and non-insulin-dependent diabetes mellitus. Metabolism 1994; 43:385-9. [PMID: 8139489 DOI: 10.1016/0026-0495(94)90109-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
To better understand abnormal insulin production (IP) in states of carbohydrate intolerance, insulin release was quantified following equimolar (2.4 mmol/kg) infusions of glucose, arginine, and valine in healthy subjects ([HS] age, 45 +/- 3 years; body mass index [BMI, kg/m2], 26.3 +/- 2.4; means +/- SEM), obese subjects with impaired glucose tolerance ([IGT] age, 43 +/- 5 years; BMI, 35.4 +/- 2.4), and non-obese patients with chronic non-insulin-dependent diabetes mellitus ([NIDDM] age, 55 +/- 3 years; BMI, 26.4 +/- 1.4; duration of disease, 13 +/- 3 years). There were eight subjects per group. Incremental IP (metabolic clearance rate of C-peptide [MCRCP] x total incremental area under the curve of plasma C-peptide [AUCCP], pmol/kg) following substrate infusion was as follows: glucose: HS, 227 +/- 14; IGT, 1,050 +/- 184 (P < .001 v HS); NIDDM, 114 +/- 27 (P < .001 v HS); arginine: HS, 139 +/- 23; IGT, 488 +/- 106 (P < .01 v HS); NIDDM, 206 +/- 47; and valine: HS, 21 +/- 7; IGT, 32 +/- 10; NIDDM, 54 +/- 12 (P < .01 v HS). The fractional clearance rate ([FCR] k, %/min) was impaired in IGT and NIDDM for glucose (HS, 3.9 +/- 0.4; IGT, 2.3 +/- 0.3 [P < .01 v HS]; NIDDM, 1.4 +/- 0.1 [P < .001 v HS]), arginine (2.4 +/- 0.1; 1.9 +/- 0.2 [P < .01 v HS]; 1.9 +/- 0.2 [P < .01 v HS]), and valine (0.95 +/- 0.06; 0.65 +/- 0.09 [P < .05 v HS]; 0.74 +/- 0.1 [P < .05 v HS]).(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- P Fasching
- Department of Internal Medicine III, University of Vienna, Austria
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Barrett EJ, Liu Z. Hepatic glucose metabolism and insulin resistance in NIDDM and obesity. BAILLIERE'S CLINICAL ENDOCRINOLOGY AND METABOLISM 1993; 7:875-901. [PMID: 8304916 DOI: 10.1016/s0950-351x(05)80238-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- E J Barrett
- University of Virginia Diabetes Center, Charlottesville 22908
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32
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Aoki TT, Benbarka MM, Okimura MC, Arcangeli MA, Walter RM, Wilson LD, Truong MP, Barber AR, Kumagai LF. Long-term intermittent intravenous insulin therapy and type 1 diabetes mellitus. Lancet 1993; 342:515-8. [PMID: 8102666 DOI: 10.1016/0140-6736(93)91645-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
An important defect in insulin-dependent diabetes mellitus (IDDM) is that the liver does not meet its full fuel-processing function, because many of the enzymes involved depend on high insulin concentrations in the portal vein. We tried to reactivate the liver by long-term treatment of IDDM patients with intravenous insulin in pulses, with the aim of achieving high portal-vein concentrations during and after a glucose meal. We studied 20 IDDM patients with brittle disease; despite use of a four-injection regimen with manipulation of insulin doses, diet, and physical activity, and frequent clinic visits for at least a year, these patients still had wide swings in blood glucose and frequent hypoglycaemic reactions. The intermittent therapy consisted of 7-10 pulses of intravenous insulin, infused while the patient was ingesting carbohydrate, primarily glucose, during the first hour of a 3 h treatment; three treatments were given in a day. After 2 consecutive days' treatment, patients were treated for 1 day per week. No patient was withdrawn from the study. At the time of this analysis the duration of intermittent treatment ranged from 7 to 71 months (mean 41 [SE 5] months). Haemoglobin A1C concentrations declined from 8.5 (0.4)% at the end of the stabilisation phase to 7.0 (0.2)% at the analysis point (p = 0.0003). During the same time the frequencies of major and minor hypoglycaemic events also fell significantly (major 3.0 [1.1] to 0.1 [0], minor 13.0 [2.6] to 2.4 [0.8] per month; both p < 0.0001). Because the use of saline rather than insulin pulses would have led to unacceptable hyperglycaemia we opted for a historical control design. The absence of a true control group limits the interpretation of these preliminary results, but we believe further studies of hepatic and muscle metabolism before and after long-term intermittent intravenous insulin therapy would be worth while.
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Affiliation(s)
- T T Aoki
- Department of Internal Medicine, University of California, Davis
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Pye S, Watarai T, Davies G, Radziuk J. Comparison of the continuously calculated fractional splanchnic extraction of insulin with its fractional disappearance using a new double-tracer technique. Metabolism 1993; 42:145-53. [PMID: 8474310 DOI: 10.1016/0026-0495(93)90028-m] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
These studies were designed to calculate the fractional disappearance rate (FDR) and splanchnic extraction of insulin in response to an exogenous (intraperitoneal) input of insulin. A double-tracer technique using insulin tritiated on both the A1 and B1 positions was introduced for the measurement of hepatic extraction. The A1 tracer, not previously characterized in vivo, was compared in terms of its kinetics with H3-B1-insulin and unlabeled insulin. The metabolic clearance rates (MCR) of the three insulins were identical, as were the decay curves of the two tracers. To measure splanchnic insulin extraction, one tracer was infused systemically to evaluate the FDR of insulin, and the second was infused into the splanchnic circulation (superior mesenteric artery) and its peripheral appearance was calculated. Splanchnic extraction was determined from the difference between this rate of appearance and the rate of infusion of the mesenteric tracer. After intraperitoneal insulin injection, insulin levels increased to peaks of 549 +/- 93 microU/mL (portal vein) and 473 +/- 99 microU/mL (inferior vena cava) and decreased to basal levels over 3 hours. The FDR decreased from 0.295 +/- 0.051 min-1 to 0.125 +/- 0.026 min-1, and splanchnic extraction decreased from 0.534 +/- 0.06 to 0.232 +/- 0.088. The latter returned to near-basal values more rapidly than did the FDR. In conclusion, the kinetics of insulin both in and out of the steady state have been shown to be nonlinear through physiological insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- S Pye
- Department of Medicine, McGill University, Montreal, Quebec, Ontario, Canada
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Morishima T, Pye S, Bradshaw C, Radziuk J. Posthepatic rate of appearance of insulin: measurement and validation in the nonsteady state. THE AMERICAN JOURNAL OF PHYSIOLOGY 1992; 263:E772-9. [PMID: 1415699 DOI: 10.1152/ajpendo.1992.263.4.e772] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
To assess the accuracy with which insulin appearance rates in the peripheral circulation can be measured out of steady state, seven conscious dogs were simultaneously infused with somatostatin and insulin at known variable rates. Tritiated insulin was infused concurrently at a constant rate. Insulin rates of appearance were estimated continuously on the basis of a two-compartment model for systemic insulin kinetics. The calculations were performed assuming that insulin kinetics were linear (tracer data not used) and nonlinear or time varying (tracer data used to assess the variation). The average error in areas under the curve was -3.5 +/- 2.5 and 27.0 +/- 14.2% when nonlinear or linear kinetics were assumed. The maximal errors when linearity was assumed was 39.9 +/- 11.3% and decreased to 16.3 +/- 2.6% when the tracer data was used to account for changes in the fractional removal rate of insulin. The accuracy of the linear estimates improved as the fractional removal rate remained closer to constant. These data suggest that a priori assumptions should not be made on the linearity of the insulin system in a given experimental situation.
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Affiliation(s)
- T Morishima
- Department of Medicine, Royal Victoria Hospital, Montreal, Quebec, Canada
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Ratheiser K, Komjati M, Gasic S, Bratusch-Marrain P, Waldhäusl W. Effect of stress hormones on transsplanchnic balance of exogenous amino acid in healthy man. Metabolism 1991; 40:1298-304. [PMID: 1961124 DOI: 10.1016/0026-0495(91)90032-r] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The effect of stress hormones on transsplanchnic balance of basal and infused amino acids (AA: Val,Met,Ile,Leu,Phe,Lys,His) was investigated in healthy men without and with added epinephrine (EPI) and dexamethasone (DEX). Concentrations of AA and blood glucose were measured in arterial and hepatic venous blood before and after primed-continuous (t = 120 minutes) AA infusion without (group I: controls; n = 6, 24 +/- 3 years), and with intravenous (IV) EPI infusion (group II: 6 micrograms/min, t = -75 to 120 minutes; n = 6, 26 +/- 5 years) or oral DEX pretreatment (group III: 6 mg/d for 2 days; n = 7, 26 +/- 3 years). In the absence of exogenous AA, EPI was demonstrated to increase estimated hepatic plasma flow (EHPF, mL/min: 1,019 +/- 133 [mean +/- SD] v 737 +/- 153; P less than .01), splanchnic output of glucose (SGO), and splanchnic uptake of total AA (nmol/kg.min: 4,657 +/- 2,014 v 2,802 +/- 704; P less than .05), of Gln (+78%) and of Gly (+100%). DEX did not affect EHPF or SGO, but doubled basal splanchnic AA uptake (5,446 +/- 3,635 nmol/kg.min) and increased that of Gln by 110%. Following AA administration, total splanchnic AA uptake was consistently increased (group I, 8,577 +/- 2,380; II, 8,957 +/- 3,714; III, 10,757 +/- 2,689 nmol/kg.min) as was splanchnic Gln uptake, both of which did not differ versus controls following EPI or DEX exposure. However, metabolic clearance rate (MCR, L/min) of infused AA was elevated by 40% (Met) to 85% (Leu) versus controls in subjects receiving EPI, but unchanged in those receiving oral DEX.(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- K Ratheiser
- Division of Endocrinology and Diabetology, I. Medizinische Universitätsklinik, Vienna, Austria
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Cavallo-Perin P, Estivi P, Boine L, Galletti R, Pacini G, Cobelli C, Pagano G. Benfluorex and blood glucose control in non insulin-dependent diabetic patients. J Endocrinol Invest 1991; 14:109-13. [PMID: 2061566 DOI: 10.1007/bf03350279] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Benfluorex has been reported to decrease blood glucose in different dismetabolic conditions, particularly in noninsulin-dependent diabetic (NIDD) patients, but the mechanism of this effect is poorly known. We evaluate fasting glucose production (3H-glucose infusion) and B-cell secretion (phi 1, phi 2 and glucose utilization SI) (minimal model technique) in 7 mild, diet treated, NIDDM patients after 6-week administration of benfluorex (450 mg/day) and placebo, in random sequence and double blind design. Body weight, HbA1c, plasma glucose profile, fasting plasma insulin, lactate, pyruvate, beta-OH-butyrate, total cholesterol, HDL-cholesterol and triglycerides were also measured at the end of each treatment. Mean values of body weight (71 +/- 4 vs 69 +/- 4 kg, p less than 0.01), HbA1c (8.3 +/- 0.2 vs 7.7 +/- 0.2%, p less than 0.01), fasting plasma glucose (137.0 +/- 6.5 vs 121.4 +/- 5.6 mg/dl, p less than 0.01), lactate (1.82 +/- 0.13 vs 1.22 +/- 0.11 mmol/l, p less than 0.0025) pyruvate (0.164 +/- 0.011 vs 0.095 +/- 0.010 mmol/l, p less than 0.0005), and beta-OH-butyrate (0.91 +/- 0.06 vs 0.66 +/- 0.04 mmol/l, p less than 0.005) were significantly lower after benfluorex than after placebo. phi 1, phi 2 and SI values were not significantly different in the two treatments. Fasting glucose production was significantly lower after benfluorex than after placebo: 2.46 +/- 1.57 vs 1.84 +/- 0.85 mg/kg.min, p less than 0.02. These results demonstrate that 6-week treatment with benfluorex produces a significant blood glucose lowering effect in mild NIDDM patients, mainly by decreasing glucose production.
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Ratheiser K, Reitgruber W, Komjati M, Bratusch-Marrain P, Vierhapper H, Waldhäusl WK. Quantitative and qualitative differences in basal and glucose- and arginine-stimulated insulin secretion in healthy subjects and different stages of NIDDM. ACTA DIABETOLOGICA LATINA 1990; 27:197-213. [PMID: 2075783 DOI: 10.1007/bf02581332] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
To determine quantitative and qualitative differences in insulin secretion equimolar amounts of glucose and arginine were infused in 9 healthy subjects, in 8 individuals each with obesity without and with impaired glucose tolerance, and in non-obese and obese non-insulin-dependent diabetic patients (NIDDM). Insulin secretion was calculated after individual determination of metabolic clearance rate of C-peptide (MCRcp) both as the area under the C-peptide concentration curve times MCRcp, and by a mono-compartment mathematical model, both yielding identical results. MCRcp fell consistently with increasing C-peptide infusion rate (e.g.: healthy subjects: C-peptide, 10 nmol/h, 4.2 +/- 0.4; 20 nmol/h, 3.3 +/- 0.3; 30 nmol/h, 3.1 +/- 0.2 ml/kg.min; p less than 0.05 to p less than 0.01). Basal insulin secretion was 2.1-fold greater in the obese with impaired glucose tolerance than in healthy subjects, but was unchanged in non-obese NIDDM. Glucose and arginine triggered insulin release was greater than in healthy subjects at almost identical area under the respective substrate concentration curve (AUC/kg body weight) in obese subjects without (2-fold) and with impaired glucose tolerance (4-fold), and in NIDDMs following i.v. arginine (2-fold). The mean ratio of incremental insulin release to i.v. glucose and arginine was smaller in NIDDM (normal weight, 1.3 +/- 0.4; obese, 1.0 +/- 0.2) than in healthy (2.0 +/- 0.3), or obese subjects with impaired glucose tolerance (2.8 +/- 0.7). Stimulated C-peptide/insulin ratio was reduced in all patients vs that in healthy subjects (p less than 0.05). We conclude that (a) MCR of C-peptide is in part a saturable process; (b) insulin clearance may be impaired in obesity and NIDDM; and (c) insulin secretion differs in obese states and NIDDM both quantitatively and qualitatively, and thereby separates the two disorders as different entities. In addition, quantitation of insulin release in obese states may also help (d) to better define primary algorithms for insulin replacement in normal- and overweight insulin-dependent diabetic patients.
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Affiliation(s)
- K Ratheiser
- Division of Clinical Endocrinology and Diabetology, 1. Medizinische Universitätsklinik, Wien, Austria
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Broussolle C, Orgiazzi J, Noël G. [Physiopathology of non-insulin-dependent diabetes: current data and therapeutic consequences]. Rev Med Interne 1990; 11:142-8. [PMID: 2204978 DOI: 10.1016/s0248-8663(05)82216-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Non insulin-dependent diabetes mellitus results from the combination in varying proportions of low plasma insulin levels (insulinopenia), peripheral resistance to insulin and increased hepatic glucose production. Abnormalities of insulin secretion can be demonstrated without and after stimulation. Insulin resistance mainly occurs in skeletal muscle and is primarily due to a "postreceptor" defect. A pancreatic peptide, amylin, may participate in insulin resistance. Hepatic glucose production correlates with high fasting plasma glucose concentrations. Whatever its initial mechanism, hyperglycaemia maintains low insulin secretion and insulin resistance by its toxicity. In the light of these data, the effects of weight loss in obese non insulin-dependent diabetics have become clearer. The action of biguanides on insulin sensitivity is confirmed. Sulphonylureas have a pancreatic and an extrapancreatic action. The normoglycaemia obtained by intermittent insulin therapy can break the vicious circle of glucose toxicity. The use of prolonged insulin therapy is discussed. Finally, new compounds with an original mode of action offer hopes for the future.
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Affiliation(s)
- C Broussolle
- Service de Médecine Interne, Centre Hospitalier Lyon Sud, Pierre-Bénite
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Prando R, Cheli V, Buzzo P, Melga P, Ansaldi E, Accoto S. Blood lactate behavior after glucose load in diabetes mellitus. ACTA DIABETOLOGICA LATINA 1988; 25:247-56. [PMID: 3071066 DOI: 10.1007/bf02624820] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The aim of this study was to evaluate the relationships between blood lactate and plasma glucose, insulin (IRI) and C-peptide (IRCP) during the first hour of an oral glucose load (OGTT, 100 g). Twelve controls, sixteen non-insulin-dependent (NIDDM) and four insulin-dependent (IDDM) diabetic subjects were studied. A significant increase in blood lactate was observed at 15 min in normal subjects, whereas there was a delayed increase at 45 min in NIDDM subjects, in the presence of IRCP increments of 0.31 nmol/l. In order to have a minimum significant lactate increment, the threshold value of peripheral IRCP increment was about 0.30 nmol/l. In IDDM subjects, despite considerable hyperglycemia, blood lactate concentration remained unchanged throughout the test. In normal and NIDDM subjects there was a significant negative correlation between delta lactate and delta glucose (r = -0.89, p less than 0.001) and a significant positive correlation between delta lactate and delta IRCP (r = 0.78, p less than 0.001). In conclusion, hyperglycemia itself and the lack of increase in insulin secretion do not affect blood lactate increase during OGTT; blood concentration of this metabolite depends mainly on an early insulin secretion apt to enhance tissue glucose uptake and to inhibit gluconeogenesis.
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Affiliation(s)
- R Prando
- Cattedra di Malattie del Ricambio, Università di Genova, Italy
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Affiliation(s)
- R Taylor
- Department of Medicine, University of Newcastle upon Tyne, U.K
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DeFronzo RA, Ferrannini E. Regulation of hepatic glucose metabolism in humans. DIABETES/METABOLISM REVIEWS 1987; 3:415-59. [PMID: 3552529 DOI: 10.1002/dmr.5610030204] [Citation(s) in RCA: 125] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Ferrannini E, Cobelli C. The kinetics of insulin in man. II. Role of the liver. DIABETES/METABOLISM REVIEWS 1987; 3:365-97. [PMID: 3552527 DOI: 10.1002/dmr.5610030202] [Citation(s) in RCA: 91] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Jackson RA, Hamling JB, Sim BM, Hawa MI, Blix PM, Nabarro JD. Peripheral lactate and oxygen metabolism in man: the influence of oral glucose loading. Metabolism 1987; 36:144-50. [PMID: 3807786 DOI: 10.1016/0026-0495(87)90008-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
We investigated the influence of oral glucose loading (100 g) on glucose, lactate, and oxygen metabolism by deep (mainly muscle) and superficial (mainly skin and adipose tissue) forearm tissues. In normal men aged 19 to 32 years (mean +/- SE, 24 +/- 1), basal arterialized venous-deep venous (A-DV) and arterialized venous-superficial venous (A-SV) plasma glucose concentration differences were 4.1 +/- 1.0 (P less than 0.001) and 4.7 +/- 1.0 (P less than 0.005) mg/dL, respectively, but increased markedly following glucose loading. During the first, second, and third hours after glucose ingestion, A-DV differences were 54 +/- 6,43 +/- 3, and 20 +/- 4 mg/dL, respectively, while the corresponding A-SV differences were 39 +/- 4, 17 +/- 2, and 8 +/- 2 mg/dL, respectively. Forearm glucose uptake by deep (FGU-D) and superficial (FGU-S) tissues basally was 0.057 +/- 0.010 and 0.012 +/- 0.002 mg/100 mL forearm/min respectively. From 15 to 180 minutes after glucose loading, mean FGU-D and FGU-S rose to 0.524 +/- 0.083 and 0.056 +/- 0.006 mg/100 mL forearm/min, respectively. Basal A, SV, and DV lactate concentrations were 0.55 +/- 0.04, 0.78 +/- 0.03, and 0.57 +/- 0.04 mmol/L, respectively (A-SV, P less than 0.001; SV-DV, P less than 0.001; A-DV, NS). Lactate production by superficial tissues (0.079 +/- 0.015 mumol/100 mL forearm/min) accounted for 62% of concurrent FGU-S.(ABSTRACT TRUNCATED AT 250 WORDS)
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Waldhäusl WK, Bratusch-Marrain P. Factors regulating the disposal of an oral glucose load in normal, diabetic, and obese subjects. DIABETES/METABOLISM REVIEWS 1987; 3:79-109. [PMID: 3568982 DOI: 10.1002/dmr.5610030105] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Kruszynska YT, Home PD, Hanning I, Alberti KG. Basal and 24-h C-peptide and insulin secretion rate in normal man. Diabetologia 1987; 30:16-21. [PMID: 3552817 DOI: 10.1007/bf01788901] [Citation(s) in RCA: 95] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
An understanding of the metabolic abnormalities rising from inappropriate insulin delivery in diabetic patients demands a knowledge of 24-h and basal insulin secretion rates in normal man. We have used biosynthetic human C-peptide to determine its kinetic parameters in 10 normal subjects and applied these to measurements of plasma concentrations in the same subjects to determine pancreatic secretion rate. Metabolic clearance rate measured by stepped primed infusion of biosynthetic human C-peptide at rates of 10, 19 and 26 nmol/h was 4.7 +/- 0.7 (+/- SD) ml X kg-1 X min-1, and was independent of infusion rate. Fractional clearance (T1/2, 26 +/- 3 min) and distribution volume (0.178 +/- 0.039 l/kg) were calculated from the decline in concentration after cessation of the highest rate infusion. Basal insulin secretion calculated from the C-peptide metabolic clearance rate and plasma concentrations for the period 02.00 to 07.00 hours was 1.3 +/- 0.4 U/h. Over 24 h total insulin secretion on a standard high carbohydrate diet was 63 +/- 15 U, calculated from the area under the C-peptide concentration curve. Basal insulin secretion, therefore, accounted for 50 +/- 8% of total insulin secretion. Although only 5.6 +/- 1.1% of C-peptide was detected in 24-h urine collections, urinary C-peptide excretion was significantly related to 24-h C-peptide secretion (r = 0.74, p less than 0.02).
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Morishima T, Pye S, Polonsky K, Radziuk J. The measurement and validation of the nonsteady-state rates of C-peptide appearance in the dog. Diabetologia 1986; 29:440-6. [PMID: 3527843 DOI: 10.1007/bf00506536] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
In order to verify the calculation of nonsteady rates of secretion of C-peptide, dog C-peptide was infused into 5 normal conscious dogs at varying rates. Using the decay curve obtained following a preliminary injection of C-peptide in each animal, concentrations during the infusion, and mathematical deconvolution, the rate of appearance of the C-peptide was calculated. This rate was within 12% of the infusion rates, with 94% of the C-peptide infused recovered in the calculation. The metabolic clearance of C-peptide was calculated to be 10.1 +/- 1.0 ml/min following both its injection and constant infusion. In conclusion, within the limits of the errors determined, C-peptide and therefore insulin secretion can be calculated on a continuous basis under nonsteady-state conditions.
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Polonsky KS, Licinio-Paixao J, Given BD, Pugh W, Rue P, Galloway J, Karrison T, Frank B. Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients. J Clin Invest 1986; 77:98-105. [PMID: 3511094 PMCID: PMC423314 DOI: 10.1172/jci112308] [Citation(s) in RCA: 235] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
We undertook this study to examine the accuracy of plasma C-peptide as a marker of insulin secretion. The peripheral kinetics of biosynthetic human C-peptide (BHCP) were studied in 10 normal volunteers and 7 insulin-dependent diabetic patients. Each subject received intravenous bolus injections of BHCP as well as constant and variable rate infusions. After intravenous bolus injections the metabolic clearance rate of BHCP (3.8 +/- 0.1 ml/kg per min, mean +/- SEM) was not significantly different from the value obtained during its constant intravenous infusion (3.9 +/- 0.1 ml/kg per min). The metabolic clearance rate of C-peptide measured during steady state intravenous infusions was constant over a wide concentration range. During experiments in which BHCP was infused at a variable rate, the peripheral concentration of C-peptide did not change in proportion to the infusion rate. Thus, the infusion rate of BHCP could not be calculated accurately as the product of the C-peptide concentration and metabolic clearance rate. However, the non-steady infusion rate of BHCP could be accurately calculated from peripheral C-peptide concentrations using a two-compartment mathematical model when model parameters were derived from the C-peptide decay curve in each subject. Application of this model to predict constant infusions of C-peptide from peripheral C-peptide concentrations resulted in model generated estimates of the C-peptide infusion rate that were 101.5 +/- 3.4% and 100.4 +/- 2.8% of low and high dose rates, respectively. Estimates of the total quantity of C-peptide infused at a variable rate over 240 min based on the two-compartment model represented 104.6 +/- 2.4% of the amount actually infused. Application of this approach to clinical studies will allow the secretion rate of insulin to be estimated with considerable accuracy. The insulin secretion rate in normal subjects after an overnight fast was 89.1 pmol/min, which corresponds with a basal 24-h secretion of 18.6 U.
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Radziuk J, Morishima T. New methods for the analysis of insulin kinetics in vivo: insulin secretion, degradation, systemic dynamics and hepatic extraction. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 1985; 189:247-76. [PMID: 3898765 DOI: 10.1007/978-1-4757-1850-8_14] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
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Niewoehner CB, Gilboe DP, Nuttall GA, Nuttall FQ. Metabolic effects of oral fructose in the liver of fasted rats. THE AMERICAN JOURNAL OF PHYSIOLOGY 1984; 247:E505-12. [PMID: 6437238 DOI: 10.1152/ajpendo.1984.247.4.e505] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Twenty-four-hour-fasted rats were given fructose (4 g/kg) by gavage. Fructose absorption and the portal vein, aorta, and hepatic vein plasma fructose, glucose, lactate, and insulin concentrations as well as liver fructose and fructose 1-P, glucose, glucose 6-P, UDPglucose, lactate, pyruvate, ATP, ADP, AMP, inorganic phosphate (Pi), cAMP, and Mg2+, and glycogen synthase I and phosphorylase alpha were measured at 10, 20, 30, 40, 60 and 120 min after gavage. Liver and muscle glycogen and serum uric acid and triglycerides also were measured. Fifty-nine percent of the fructose was absorbed in 2 h. There were modest increases in plasma and hepatic fructose, glucose, and lactate and in plasma insulin. Concentrations in the portal vein, aorta, and hepatic vein plasma indicate rapid removal of fructose and lactate by the liver and a modest increase in production of glucose. The source of the increase in plasma lactate is uncertain. Hepatic glucose 6-P increased twofold; UDPglucose rose transiently and then decreased below the control level. Fructose 1-P increased linearly to a concentration of 3.3 mumol/g wet wt by 120 min. There was no change in ATP, ADP, AMP, cAMP, Pi, or Mg2+. Serum triglycerides and uric acid were unchanged. Glycogen synthase was activated by 20 min without a change in phosphorylase alpha. This occurred with a fructose dose that did not significantly increase either the liver glucose or fructose concentrations. Liver glycogen increased linearly after 20 min, and glycogen storage was equal in liver (38.4%) and muscle (36.5%).(ABSTRACT TRUNCATED AT 250 WORDS)
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