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Diabetologia
Published in: Diabetologia 5/2004

01-05-2004 | Review

Control of glycaemia: from molecules to men. Minkowski Lecture 2003

Author: M. Stumvoll

Published in: Diabetologia | Issue 5/2004

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Abstract

Regulation of glycaemia represents a fundamental biological principle, and its failure underlies Type 2 diabetes. The complex aetiology of Type 2 diabetes, which probably involves a medley of molecular mechanisms, requires dissection out of diabetes-associated subphenotypes, such as the non-obese with increased liver fat or the obese with low plasma adiponectin. The concepts of the hyperbolic relationship of insulin secretion and insulin sensitivity with glucose allostasis help us to establish the pathophysiological framework within which such mechanisms must operate. The translation of burgeoning new basic science findings into a physiological and clinical context calls for novel and imaginative clinical experimental tools. For the purpose of this review, four molecules (adiponectin [APM1], stearoyl CoA desaturase-1 [SCD1], insulin receptor substrate-1 [IRS1], peroxisome proliferator-activated receptor-γ [PPARG]), each with a plausible role in the disease process, have been selected to illustrate the use of such techniques in humans. These include procedures as diverse as isotope dilution for turnover studies (e.g. glycerol turnover as a proxy for lipolysis), conventional and modified clamp procedures, association studies of functionally relevant single nucleotide polymorphisms in candidate genes (e.g. IRS-1 and PPARγ), multivariate correlational analyses (as with plasma adiponectin), magnetic resonance spectroscopy to quantify intra-tissue lipid deposition and regional fat distribution, and gas chromatography to determine fatty acid patterns in selected lipid fractions as proxy for intrahepatic enzyme activity. A concerted effort by scientists from many disciplines (genetics and cell biology, physiology and epidemiology) will be required to bridge the growing gap between basic scientific concepts of biological modifiers of glycaemia and concepts that are truly relevant for human Type 2 diabetes.
Literature
1.
Fajans SS, Bell GI, Polonsky KS (2001) Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 345:971–980PubMed
2.
Maassen JA, Kadowaki T (1996) Maternally inherited diabetes and deafness: a new diabetes subtype. Diabetologia 39:375–382CrossRefPubMed
3.
Pozzilli P, Di Mario U (2001) Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention. Diabetes Care 24:1460–1467PubMed
4.
Bergman RN, Phillips LS, Cobelli C (1981) Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest 68:1456–1467PubMed
5.
Bergman RN, Ader M, Huecking K et al. (2002) Accurate assessment of beta-cell function: the hyperbolic correction. Diabetes 51 [Suppl 1]:S212–S220
6.
Kahn SE, Prigeon RL, McCulloch DK et al. (1993) Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects. Evidence for a hyperbolic function. Diabetes 42:1663–1672PubMed
7.
Bergman RN (1989) Lilly lecture 1989. Toward physiological understanding of glucose tolerance. Minimal-model approach. Diabetes 38:1512–1527PubMed
8.
Stumvoll M, Tataranni PA, Stefan N et al. (2003) Glucose allostasis. Diabetes 52:903–909PubMed
9.
Cannon WB (1929) Organization for physiological homeostasis. Physiol Rev 9:399–431
10.
Sterling P, Eyer J (1988) Allostasis: a new paradigm to explain arousal pathology. In: Fisher S, Reason J (eds) Handbook of life stress, cognition and health. Wiley, New York, pp 629–649
11.
McEwen BS (1998) Protective and damaging effects of stress mediators. N Engl J Med 338:171–179
12.
Seeman TE, McEwen BS, Rowe JW et al. (2001) Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging. Proc Natl Acad Sci USA 98:4770–4775CrossRefPubMed
13.
14.
Goran MI, Gower BA (2001) Longitudinal study on pubertal insulin resistance. Diabetes 50:2444–2450PubMed
15.
Montague CT, O’Rahilly S (2000) The perils of portliness: causes and consequences of visceral adiposity. Diabetes 49:883–888
16.
Seppala-Lindroos A, Vehkavaara S, Hakkinen AM et al. (2002) Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 87:3023–3028
17.
Thamer C, Machann J, Bachmann O et al. (2003) Intramyocellular lipids: anthropometric determinants and relationships with maximal aerobic capacity and insulin sensitivity. J Clin Endocrinol Metab 88:1785–1791CrossRefPubMed
18.
Medici F, Hawa M, Pyke DA et al. (1999) Concordance rate for type II diabetes mellitus in monozygotic twins: actuarial analysis. Diabetologia 42:146–150PubMed
19.
Poulsen P, Kyvik KO, Vaag A et al. (1999) Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance—a population-based twin study. Diabetologia 42:139–145
20.
Lehtovirta M, Kaprio J, Forsblom C et al. (2000) Insulin sensitivity and insulin secretion in monozygotic and dizygotic twins. Diabetologia 43:285–293
21.
Lander ES, Schork NJ (1994) Genetic dissection of complex traits. Science 265:2037–2048PubMed
22.
Hanis CL, Boerwinkle E, Chakraborty R et al. (1996) A genome-wide search for human non-insulin-dependent (Type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 13:161–166PubMed
23.
Permutt AM, Bernal-Mizrachi E, Inoue H (2000) Calpain 10: the first positional cloning of a gene for Type 2 diabetes. J Clin Invest 106:819–821PubMed
24.
Ma H, Fukiage C, Kim YH et al. (2001) Characterization and expression of calpain 10. A novel ubiquitous calpain with nuclear localization. J Biol Chem 276:28525–28531CrossRefPubMed
25.
Baier LJ, Permana PA, Yang X et al. (2000) A calpain-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 106:R69–R73PubMed
26.
Oral EA, Simha V, Ruiz E et al. (2002) Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578PubMed
27.
Weyer C, Funahashi T, Tanaka S et al. (2001) Hypoadiponectinemia in obesity and Type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935PubMed
28.
Takahashi M, Arita Y, Yamagata K et al. (2000) Genomic structure and mutations in adipose-specific gene, adiponectin. Int J Obes Relat Metab Disord 24:861–868PubMed
29.
Yang WS, Lee WJ, Funahashi T et al. (2001) Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 86:3815–3819PubMed
30.
Lindsay RS, Funahashi T, Hanson RL et al. (2002) Adiponectin and development of Type 2 diabetes in the Pima Indian population. Lancet 360:57–58CrossRefPubMed
31.
Spranger J, Kroke A, Mohlig M et al. (2003) Adiponectin and protection against Type 2 diabetes mellitus. Lancet 361:226–228CrossRef
32.
Yamauchi T, Kamon J, Waki H et al. (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946PubMed
33.
Combs TP, Pajvani UB, Berg AH et al. (2004) A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology 145:367–383CrossRefPubMed
34.
Tschritter O, Fritsche A, Thamer C et al. (2003) Plasma adiponectin concentrations predict insulin sensitivity of both glucose and lipid metabolism. Diabetes 52:239–243PubMed
35.
Combs TP, Berg AH, Obici S et al. (2001) Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest 108:1875–1881PubMed
36.
Stefan N, Stumvoll M, Vozarova B et al. (2003) Plasma adiponectin and endogenous glucose production in humans. Diabetes Care 26:3315–3319PubMed
37.
Stumvoll M, Tschritter O, Fritsche A et al. (2002) Association of the T-G polymorphism in adiponectin (exon 2) with obesity and insulin sensitivity. Interaction with family history of diabetes. Diabetes 51:37–42PubMed
38.
Yamauchi T, Kamon J, Ito Y et al. (2003) Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423:762–769CrossRefPubMed
39.
Cohen P, Miyazaki M, Socci ND et al. (2002) Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 297:240–243CrossRefPubMed
40.
Zhang Y, Wat N, Stratton IM et al. (1996) UKPDS 19: heterogeneity in NIDDM: separate contributions of IRS-1 and beta 3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. UK Prospective Diabetes Study. Diabetologia 39:1505–1511PubMed
41.
Koch M, Rett K, Volk A et al. (1999) Amino acid polymorphism Gly 972 Arg in IRS-1 is not associated to lower clamp-derived insulin sensitivity in young healthy first degree relatives of patients with Type 2 diabetes. Exp Clin Endocrinol Diabetes 107:318–322PubMed
42.
Hager J, Zouali H, Velho G et al. (1993) Insulin receptor substrate (IRS-1) gene polymorphisms in French NIDDM families. Lancet 342:1430–1430
43.
Imai Y, Philippe N, Sesti G et al. (1997) Expression of variant forms of insulin receptor substrate-1 identified in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 82:4201–4207
44.
Ura S, Araki E, Kishikawa H et al. (1996) Molecular scanning of the insulin receptor substrate-1 (IRS-1) gene in Japanese patients with NIDDM: identification of five novel polymorphisms. Diabetologia 39:600–608
45.
Almind K, Bjorbaek C, Vestergaard H et al. (1993) Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus. Lancet 342:828–832PubMed
46.
Laakso M, Malkki M, Kekalainen P et al. (1994) Insulin receptor substrate-1 variants in non-insulin-dependent diabetes. J Clin Invest 94:1141–1146PubMed
47.
Porzio O, Federici M, Hribal ML et al. (1999) The Gly972→Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. J Clin Invest 104:357–364PubMed
48.
Stumvoll M, Fritsche A, Volk A et al. (2001) The Gly972Arg polymorphism in the insulin receptor substrate-1 gene contributes to the variation in insulin secretion in normal glucose tolerant humans. Diabetes 50:882–885PubMed
49.
Marchetti P, Lupi R, Federici M et al. (2002) Insulin secretory function is impaired in isolated human islets carrying the Gly(972)→Arg IRS-1 polymorphism. Diabetes 51:1419–1424
50.
Fritsche A, Stefan N, Hardt E et al. (2000) A novel hyperglycemic clamp for characterization of islet function in humans: assessment of three different secretagogues, maximal insulin response and reproducibility. Eur J Clin Invest 30:411–418CrossRefPubMed
51.
’t Hart LM, Nijpels G, Dekker JM et al. (2002) Variations in insulin secretion in carriers of gene variants in IRS-1 and -2. Diabetes 51:884–887PubMed
52.
Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20:649–688PubMed
53.
Stumvoll M, Haring HU (2002) Glitazones: clinical effects and molecular mechanisms. Ann Med 34:217–224PubMed
54.
Olefsky JM (2000) Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists. J Clin Invest 106:467–472PubMed
55.
56.
Saltiel AR, Olefsky JM (1996) Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 45:1661–1669PubMed
57.
Spiegelman BM (1998) PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 47:507–514PubMed
58.
59.
Beamer BA, Negri C, Yen CJ et al. (1997) Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-gamma (hPPAR gamma) gene. Biochem Biophys Res Commun 233:756–759CrossRefPubMed
60.
Yen CJ, Beamer BA, Negri C et al. (1997) Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. Biochem Biophys Res Commun 241:270–274CrossRefPubMed
61.
Altshuler D, Hirschhorn JN, Klannemark M et al. (2000) The common PPARγ Pro12Ala polymorphism is associated with decreased risk of Type 2 diabetes. Nat Genet 26:76–80PubMed
62.
Memisoglu A, Hu FB, Hankinson SE et al. (2003) Interaction between a peroxisome proliferator-activated receptor {gamma} gene polymorphism and dietary fat intake in relation to body mass. Hum Mol Genet 12:2923–2929CrossRefPubMed
63.
Ek J, Andersen G, Urhammer SA et al. (2001) Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) gene in relation to insulin sensitivity among glucose tolerant Caucasians. Diabetologia 44:1170–1176CrossRefPubMed
64.
Deeb SS, Fajas L, Nemoto M et al. (1998) A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 20:284–287CrossRefPubMed
65.
Jacob S, Stumvoll M, Becker R et al. (2000) The PPARgamma2 polymorphism Pro12Ala is associated with better insulin sensitivity in the offspring of Type 2 diabetic patients. Horm Metab Res 32:413–416PubMed
66.
Hara K, Okada T, Tobe K et al. (2000) The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to Type 2 diabetes. Biochem Biophys Res Commun 271:212–216PubMed
67.
Koch M, Rett K, Maerker E et al. (1999) The PPARgamma2 amino acid polymorphism Pro 12 Ala is prevalent in offspring of Type II diabetic patients and is associated to increased insulin sensitivity in a subgroup of obese subjects. Diabetologia 42:758–762CrossRefPubMed
68.
Muller YL, Bogardus C, Beamer BA et al. (2003) A functional variant in the peroxisome proliferator-activated receptor gamma2 promoter is associated with predictors of obesity and Type 2 diabetes in Pima Indians. Diabetes 52:1864–1871PubMed
69.
Stumvoll M, Wahl HG, Löblein K et al. (2001) The Pro12Ala polymorphism in the peroxisome proliferator activated receptor γ2 gene is associated with increased antilipolytic insulin sensitivity. Diabetes 50:876–881PubMed
70.
Boden G, Chen X, Capulong E et al. (2001) Effects of free fatty acids on gluconeogenesis and autoregulation of glucose production in Type 2 diabetes. Diabetes 50:810–816
71.
Boden G (1997) Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 46:3–10PubMed
72.
Duckworth WC, Bennett RG, Hamel FG (1998) Insulin degradation: progress and potential. Endocr Rev 19:608–624CrossRefPubMed
73.
Douglas JA, Erdos MR, Watanabe RM et al. (2001) The peroxisome proliferator-activated receptor-gamma2 Pro12A1a variant: association with Type 2 diabetes and trait differences. Diabetes 50:886–890
74.
Ferrannini E, Wahren J, Faber OK et al. (1983) Splanchnic and renal metabolism of insulin in human subjects: a dose-response study. Am J Physiol 244:E517–E527PubMed
75.
Campbell PJ, Carlson MG, Nurjhan N (1994) Fat metabolism in human obesity. Am J Physiol 266:E600–E605PubMed
76.
Iozzo P, Beck-Nielsen H, Laakso M et al. (1999) Independent influence of age on basal insulin secretion in nondiabetic humans. European Group for the Study of Insulin Resistance. J Clin Endocrinol Metab 84: 863–868CrossRefPubMed
77.
Jones CN, Pei D, Staris P et al. (1997) Alterations in the glucose-stimulated insulin secretory dose-response curve and in insulin clearance in nondiabetic insulin-resistant individuals. J Clin Endocrinol Metab 82:1834–1838CrossRefPubMed
78.
Luan J, Browne PO, Harding AH et al. (2001) Evidence for gene-nutrient interaction at the PPARgamma locus. Diabetes 50:686–689PubMed
79.
Mori H, Ikegami H, Kawaguchi Y et al. (2001) The Pro12 -->Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with Type 2 diabetes. Diabetes 50:891–894PubMed
80.
Bergman RN (2000) Non-esterified fatty acids and the liver: why is insulin secreted into the portal vein? Diabetologia 43:946–952PubMed
81.
Michael MD, Kulkarni RN, Postic C et al. (2000) Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Mol Cell 6:87–97PubMed
82.
Chen X, Iqbal N, Boden G (1999) The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects. J Clin Invest 103:365–372PubMed
83.
Tschritter O, Fritsche A, Stefan N et al. (2003) Increased insulin clearance in peroxisome proliferator-activated receptor gamma2 Pro12Ala. Metabolism 52:778–783CrossRefPubMed
84.
Poy MN, Yang Y, Rezaei K et al. (2002) CEACAM1 regulates insulin clearance in liver. Nat Genet 30:270–276CrossRefPubMed
85.
Stumvoll M, Mitrakou A, Pimenta W et al. (2000) Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care 23:295–301
86.
Matsuda A, DeFronzo R (1999) Insulin sensitivity indices obtained from oral glucose tolerance testing. Diabetes Care 22:1462–1470PubMed
87.
Stumvoll M, Häring H (2002) The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor γ. Diabetes 51:2341–2347
Metadata
Title
Control of glycaemia: from molecules to men. Minkowski Lecture 2003
Author
M. Stumvoll
Publication date
01-05-2004
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 5/2004
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-004-1400-0

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