Skip to main content
Top

05-02-2017 | Obesity | Review | Article

Hyperinsulinemia: a Cause of Obesity?

Journal: Current Obesity Reports

Authors: Karel A. Erion, Barbara E. Corkey

Publisher: Springer US

Abstract

Purpose of Review

This perspective is motivated by the need to question dogma that does not work: that the problem is insulin resistance (IR). We highlight the need to investigate potential environmental obesogens and toxins.

Recent Findings

The prequel to severe metabolic disease includes three interacting components that are abnormal: (a) IR, (b) elevated lipids and (c) elevated basal insulin (HI). HI is more common than IR and is a significant independent predictor of diabetes.

Summary

We hypothesize that (1) the initiating defect is HI that increases nutrient consumption and hyperlipidemia (HL); (2) the cause of HI may include food additives, environmental obesogens or toxins that have entered our food supply since 1980; and (3) HI is sustained by HL derived from increased adipose mass and leads to IR. We suggest that HI and HL are early indicators of metabolic dysfunction and treating and reversing these abnormalities may prevent the development of more serious metabolic disease.
Literature
1.
Levine JA, Eberhardt NL, Jensen MD. Role of nonexercise activity thermogenesis in resistance to fat gain in humans. Science (New York, N Y ). 1999;283(5399):212–4.CrossRef
2.
•• Schlogl M, Piaggi P, Pannacciuli N, Bonfiglio SM, Krakoff J, Thearle MS. Energy expenditure responses to fasting and overfeeding identify phenotypes associated with weight change. Diabetes. 2015;64(11):3680–9. A decrease in 24-h energy expenditure during fasting and an increase with overfeeding correlated with a larger reduction in weight gain during fasting; a smaller response to low-protein overfeeding and a larger response to high-carbohydrate overfeeding correlated with weight gain CrossRefPubMedPubMedCentral
3.
•• Fothergill E, Guo J, Howard L, Kerns JC, Knuth ND, Brychta R, et al. Persistent metabolic adaptation 6 years after “The Biggest Loser” competition. Obesity (Silver Spring). 2016;24(8):1612–9. doi:10.​1002/​oby.​21538. Fourteen of the 16 “Biggest Loser” competitors participated in a follow-up study. Weight loss at the end of the competition averaged 58.3, and RMR decreased by 610 kcal/day. After 6 years, 41.0 kg of the lost weight was regained, while RMR was 704 kcal/day below baseline and metabolic adaptation was −499 kcal/day CrossRef
4.
Ludvik B, Nolan JJ, Baloga J, Sacks D, Olefsky J. Effect of obesity on insulin resistance in normal subjects and patients with NIDDM. Diabetes. 1995;44(9):1121–5.CrossRefPubMed
5.
Moro E, Gallina P, Pais M, Cazzolato G, Alessandrini P, Bittolo-Bon G. Hypertriglyceridemia is associated with increased insulin resistance in subjects with normal glucose tolerance: evaluation in a large cohort of subjects assessed with the 1999 World Health Organization criteria for the classification of diabetes. Metabolism. 2003;52(5):616–9. doi:10.​1053/​meta.​2003.​50102.CrossRefPubMed
6.
Corkey BE. Diabetes: have we got it all wrong? Insulin hypersecretion and food additives: cause of obesity and diabetes? Diabetes Care. 2012;35(12):2432–7. doi:10.​2337/​dc12-0825.CrossRefPubMedPubMedCentral
7.
Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). J Clin Invest. 1997;100(5):1166–73. doi:10.​1172/​JCI119628.CrossRefPubMedPubMedCentral
8.
Weyer C, Hanson RL, Tataranni PA, Bogardus C, Pratley RE. A high fasting plasma insulin concentration predicts type 2 diabetes independent of insulin resistance: evidence for a pathogenic role of relative hyperinsulinemia. Diabetes. 2000;49(12):2094–101.CrossRefPubMed
9.
McGarry JD. What if Minkowski had been ageusic? An alternative angle on diabetes. Science. 1992;258(5083):766–70.CrossRefPubMed
10.
Williams KJ, Wu X. Imbalanced insulin action in chronic over nutrition: clinical harm, molecular mechanisms, and a way forward. Atherosclerosis. 2016;247:225–82. doi:10.​1016/​j.​atherosclerosis.​2016.​02.​004.CrossRefPubMed
11.
Bessesen DH. Regulation of body weight: what is the regulated parameter? Physiol Behav. 2011;104(4):599–607.CrossRefPubMed
12.
Hill JO, Wyatt HR, Reed GW, Peters JC. Obesity and the environment: where do we go from here? Science (New York, N Y ). 2003;299(5608):853–5.CrossRef
13.
Leroux L, Desbois P, Lamotte L, Duvillie B, Cordonnier N, Jackerott M, et al. Compensatory responses in mice carrying a null mutation for Ins1 or Ins2. Diabetes. 2001;50(Suppl 1):S150–3.CrossRefPubMed
14.
Mehran AE, Templeman NM, Brigidi GS, Lim GE, Chu KY, Hu X, et al. Hyperinsulinemia drives diet-induced obesity independently of brain insulin production. Cell Metab. 2012;16(6):723–37. doi:10.​1016/​j.​cmet.​2012.​10.​019.CrossRefPubMed
15.
Templeman NM, Clee SM, Johnson JD. Suppression of hyperinsulinaemia in growing female mice provides long-term protection against obesity. Diabetologia. 2015;58(10):2392–402. doi:10.​1007/​s00125-015-3676-7.CrossRefPubMedPubMedCentral
16.
D'Souza AM, Johnson JD, Clee SM, Kieffer TJ. Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetes in leptin-deficient Lepob/ob mice. Mol Metab. 2016;5(11):1103–12. doi:10.​1016/​j.​molmet.​2016.​09.​007.CrossRefPubMedPubMedCentral
17.
•• Templeman NM, Skovso S, Page MM, Lim GE, Johnson JD. A causal role for hyperinsulinemia in obesity. J Endocrinol. 2017; doi:10.​1530/​JOE-16-0449. This review discusses theoretical considerations around the causal role of excess insulin in obesity; new evidence demonstrating that modest reductions in circulating insulin prevent weight gain, with sustained effects that can persist after insulin levels normalize. Importantly, evidence from long-term studies reveals that a modest reduction in circulating insulin is not associated with impaired glucose homeostasis, meaning that body weight and lipid homeostasis are actually more sensitive to small changes in circulating insulin than glucose homeostasis in animal models PubMed
18.
Wilson TJ, Kola I. The LoxP/CRE system and genome modification. Methods Mol Biol. 2001;158:83–94. doi:10.​1385/​1-59259-220-1:​83.PubMed
19.
Kitamura T, Kahn CR, Accili D. Insulin receptor knockout mice. Annu Rev Physiol. 2003;65:313–32. doi:10.​1146/​annurev.​physiol.​65.​092101.​142540.CrossRefPubMed
20.
Bluher M, Michael MD, Peroni OD, Ueki K, Carter N, Kahn BB, et al. Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell. 2002;3(1):25–38.CrossRefPubMed
21.
Liu HY, Hong T, Wen GB, Han J, Zuo D, Liu Z, et al. Increased basal level of Akt-dependent insulin signaling may be responsible for the development of insulin resistance. Am J Physiol Endocrinol Metab. 2009;297(4):E898–906. doi:10.​1152/​ajpendo.​00374.​2009.CrossRefPubMedPubMedCentral
22.
Koch L, Wunderlich FT, Seibler J, Konner AC, Hampel B, Irlenbusch S, et al. Central insulin action regulates peripheral glucose and fat metabolism in mice. J Clin Invest. 2008;118(6):2132–47. doi:10.​1172/​JCI31073.PubMedPubMedCentral
23.
Klockener T, Hess S, Belgardt BF, Paeger L, Verhagen LA, Husch A, et al. High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat Neurosci. 2011;14(7):911–8. doi:10.​1038/​nn.​2847.CrossRefPubMedPubMedCentral
24.
Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, et al. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A. 2004;101(9):3100–5. doi:10.​1073/​pnas.​0308724101.CrossRefPubMedPubMedCentral
25.
Ning J, Hong T, Yang X, Mei S, Liu Z, Liu HY, et al. Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse. Am J Physiol Endocrinol Metab. 2011;301(2):E391–401. doi:10.​1152/​ajpendo.​00164.​2011.CrossRefPubMedPubMedCentral
26.
Ortega-Molina A, Lopez-Guadamillas E, Mattison JA, Mitchell SJ, Munoz-Martin M, Iglesias G, et al. Pharmacological inhibition of PI3K reduces adiposity and metabolic syndrome in obese mice and rhesus monkeys. Cell Metab. 2015;21(4):558–70. doi:10.​1016/​j.​cmet.​2015.​02.​017.CrossRefPubMed
27.
Reaven GM. Insulin resistance: the link between obesity and cardiovascular disease. Med Clin North Am. 2011;95(5):875–92. doi:10.​1016/​j.​mcna.​2011.​06.​002.CrossRefPubMed
28.
Gallagher EJ, Leroith D, Karnieli E. Insulin resistance in obesity as the underlying cause for the metabolic syndrome. Mt Sinai J Med. 2010;77(5):511–23. doi:10.​1002/​msj.​20212.CrossRefPubMed
29.
Robertson RP, Harmon J, Tran PO, Poitout V. Beta-cell glucose toxicity, lipotoxicity, and chronic oxidative stress in type 2 diabetes. Diabetes. 2004;53(Suppl 1):S119–24.CrossRefPubMed
30.
Wang RH, Kim HS, Xiao C, Xu X, Gavrilova O, Deng CX. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest. 2011;121(11):4477–90. doi:10.​1172/​JCI46243.CrossRefPubMedPubMedCentral
31.
Savage DB, Petersen KF, Shulman GI. Mechanisms of insulin resistance in humans and possible links with inflammation. Hypertension. 2005;45(5):828–33. doi:10.​1161/​01.​HYP.​0000163475.​04421.​e4.CrossRefPubMed
32.
Corkey BE, Shirihai O. Metabolic master regulators: sharing information among multiple systems. Trends Endocrinol Metab. 2012; doi:10.​1016/​j.​tem.​2012.​07.​006.PubMedPubMedCentral
33.
Salinari S, Bertuzzi A, Iaconelli A, Manco M, Mingrone G. Twenty-four hour insulin secretion and beta cell NEFA oxidation in type 2 diabetic, morbidly obese patients before and after bariatric surgery. Diabetologia. 2008;51(7):1276–84.CrossRefPubMed
34.
Pories WJ, Dohm GL. Diabetes: have we got it all wrong? Hyperinsulinism as the culprit: surgery provides the evidence. Diabetes Care. 2012;35(12):2438–42. doi:10.​2337/​dc12-0684.CrossRefPubMedPubMedCentral
35.
Porte Jr D, Baskin DG, Schwartz MW. Insulin signaling in the central nervous system: a critical role in metabolic homeostasis and disease from C. elegans to humans. Diabetes. 2005;54(5):1264–76.CrossRefPubMed
36.
Vogt MC, Bruning JC. CNS insulin signaling in the control of energy homeostasis and glucose metabolism—from embryo to old age. Trends Endocrinol Metab. 2013;24(2):76–84. doi:10.​1016/​j.​tem.​2012.​11.​004.CrossRefPubMed
37.
Karmi A, Iozzo P, Viljanen A, Hirvonen J, Fielding BA, Virtanen K, et al. Increased brain fatty acid uptake in metabolic syndrome. Diabetes. 2010;59(9):2171–7. doi:10.​2337/​db09-0138.CrossRefPubMedPubMedCentral
38.
Moriarty-Craige SE, Jones DP. Extracellular thiols and thiol/disulfide redox in metabolism. Annu Rev Nutr. 2004;24:481–509. doi:10.​1146/​annurev.​nutr.​24.​012003.​132208.CrossRefPubMed
39.
•• Jones Iv AR, Meshulam T, Oliveira MF, Burritt N, Corkey BE. Extracellular redox regulation of intracellular reactive oxygen generation, mitochondrial function and lipid turnover in cultured human adipocytes. PLoS One. 2016;11(10):e0164011. This study provides the first evidence that changes in redox outside human adipocytes is translated to modification of intracellular lipid handling and bioenergetics CrossRefPubMedPubMedCentral
40.
• Nocito L, Kleckner AS, Yoo EJ, Jones Iv AR, Liesa M, Corkey BE. The extracellular redox state modulates mitochondrial function, gluconeogenesis, and glycogen synthesis in murine hepatocytes. PLoS One. 2015;10(3):e0122818. doi:10.​1371/​journal.​pone.​0122818. This study provides the first evidence that changes in redox outside rodent hepatocytes is translated to modification of intracellular glucose handling CrossRefPubMedPubMedCentral
41.
Wang X, Tao L, Hai CX. Redox-regulating role of insulin: the essence of insulin effect. Mol Cell Endocrinol. 2012;349(2):111–27.CrossRefPubMed
42.
Karpe F, Dickmann JR, Frayn KN. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes. 2011;60(10):2441–9. doi:10.​2337/​db11-0425.CrossRefPubMedPubMedCentral
43.
Bessesen DH, Rupp CL, Eckel RH. Dietary fat is shunted away from oxidation, toward storage in obese Zucker rats. Obes Res. 1995;3:179–89.CrossRefPubMed
44.
• de Lima-Junior JC, Velloso LA, Geloneze B. The obese brain—effects of bariatric surgery on energy balance neurocircuitry. Curr Atheroscler Rep. 2015;17(10):57. doi:10.​1007/​s11883-015-0536-3. A review of the mechanisms by which Roux-en-Y gastric bypass can change peripheral signals that modulate melanocortin circuits involved in the regulation of energy balance CrossRefPubMedPubMedCentral
45.
Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J. 1922;12(3):141–6.PubMedPubMedCentral
46.
MacKay EM, Callaway JW. Hyperalimentation in normal animals produced by protamine insulin. Proc Soc Exp Biol Med. 1937;36(3):406–7.CrossRef
47.
Beaton GH, Curry DM. A comparison of the effects of growth hormone and of insulin administration. Endocrinology. 1956;58(6):797–801. doi:10.​1210/​endo-58-6-797.CrossRefPubMed
48.
Wagner EM, Scow RO. Effect of insulin on growth in force-fed hypophysectomized rats. Endocrinology. 1957;61(4):419–25. doi:10.​1210/​endo-61-4-419.CrossRefPubMed
49.
Hausberger FX, Hausberger BC. Effect of insulin and cortisone on weight gain, protein and fat content of rats. Am J Phys. 1958;193(3):455–60.
50.
Renold AE, Marble A, Fawcett DW. Action of insulin on deposition of glycogen and storage of fat in adipose tissue. Endocrinology. 1950;46(1):55–66. doi:10.​1210/​endo-46-1-55.CrossRefPubMed
51.
Hales CN, Kennedy GC. Plasma glucose, non-esterified fatty acid and insulin concentrations in hypothalamic-hyperphagic rats. Biochem J. 1964;90(3):620–4.CrossRefPubMedPubMedCentral
52.
York DA, Bray GA. Dependence of hypothalamic obesity on insulin, the pituitary and the adrenal gland. Endocrinology. 1972;90(4):885–94. doi:10.​1210/​endo-90-4-885.CrossRefPubMed
53.
Han PW, Frohman LA. Hyperinsulinemia in tube-fed hypophysectomized rats bearing hypothalamic lesions. Am J Phys. 1970;219(6):1632–6.
54.
Goldman JK, Bernardis LL, Frohman LA. Food intake in hypothalamic obesity. Am J Phys. 1974;227(1):88–91.
55.
Frohman LA, Bernardis LL, Schnatz JD, Burek L. Plasma insulin and triglyceride levels after hypothalamic lesions in weanling rats. Am J Phys. 1969;216(6):1496–501.
56.
Hustvedt BE, Lovo A. Correlation between hyperinsulinemia and hyperphagia in rats with ventromedial hypothalamic lesions. Acta Physiol Scand. 1972;84(1):29–33. doi:10.​1111/​j.​1748-1716.​1972.​tb05152.​x.CrossRefPubMed
57.
Chikamori K, Masuda K, Izumi H, Isaka K, Tezuka U. Effect of vagotomy on hyperinsulinemia in obese rats with hypothalamic lesions. Endocrinol Jpn. 1977;24(3):251–8.CrossRefPubMed
58.
Sonoda T. Hyperinsulinemia and its role in maintaining the hypothalamic hyperphagia in chickens. Physiol Behav. 1983;30(3):325–9.CrossRefPubMed
59.
Larue-Achagiotis C, Le Magnen J. Effects of a diazoxide inhibition of insulin release on food intake of normal and hyperphagic hypothalamic rats. Pharmacol Biochem Behav. 1978;9(6):717–20.CrossRefPubMed
60.
Lustig RH, Rose SR, Burghen GA, Velasquez-Mieyer P, Broome DC, Smith K, et al. Hypothalamic obesity caused by cranial insult in children: altered glucose and insulin dynamics and reversal by a somatostatin agonist. J Pediatr. 1999;135(2 Pt 1):162–8.CrossRefPubMed
61.
Lustig RH, Hinds PS, Ringwald-Smith K, Christensen RK, Kaste SC, Schreiber RE, et al. Octreotide therapy of pediatric hypothalamic obesity: a double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2003;88(6):2586–92. doi:10.​1210/​jc.​2002-030003.CrossRefPubMed
62.
Kieffer TJ, Heller RS, Leech CA, Holz GG, Habener JF. Leptin suppression of insulin secretion by the activation of ATP-sensitive K+ channels in pancreatic beta-cells. Diabetes. 1997;46(6):1087–93.CrossRefPubMedPubMedCentral
63.
Laubner K, Kieffer TJ, Lam NT, Niu X, Jakob F, Seufert J. Inhibition of preproinsulin gene expression by leptin induction of suppressor of cytokine signaling 3 in pancreatic beta-cells. Diabetes. 2005;54(12):3410–7.CrossRefPubMed
64.
Godbole VY, Grundleger ML, Thenen SW. Early development of lipogenesis in genetically obese (ob/ob) mice. Am J Phys. 1980;239(4):E265–E8.
65.
Gray SL, Donald C, Jetha A, Covey SD, Kieffer TJ. Hyperinsulinemia precedes insulin resistance in mice lacking pancreatic beta-cell leptin signaling. Endocrinology. 2010;151(9):4178–86. doi:10.​1210/​en.​2010-0102.CrossRefPubMed
66.
Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, et al. Effects of the obese gene product on body weight regulation in ob/ob mice. Science. 1995;269(5223):540–3.CrossRefPubMed
67.
Levin N, Nelson C, Gurney A, Vandlen R, de Sauvage F. Decreased food intake does not completely account for adiposity reduction after ob protein infusion. Proc Natl Acad Sci U S A. 1996;93(4):1726–30.CrossRefPubMedPubMedCentral
68.
Alemzadeh R, Jacobs W, Pitukcheewanont P. Antiobesity effect of diazoxide in obese Zucker rats. Metabolism. 1996;45(3):334–41.CrossRefPubMed
69.
Alemzadeh R, Slonim AE, Zdanowicz MM, Maturo J. Modification of insulin resistance by diazoxide in obese Zucker rats. Endocrinology. 1993;133(2):705–12. doi:10.​1210/​endo.​133.​2.​8344209.CrossRefPubMed
70.
Camastra S, Gastaldelli A, Mari A, Bonuccelli S, Scartabelli G, Frascerra S, et al. Early and longer term effects of gastric bypass surgery on tissue-specific insulin sensitivity and beta cell function in morbidly obese patients with and without type 2 diabetes. Diabetologia. 2011;54(8):2093–102. doi:10.​1007/​s00125-011-2193-6.CrossRefPubMed
71.
Cohen BM. Diabetes mellitus among Indians of the American Southwest: its prevalence and clinical characteristics in a hospitalized population. Ann Intern Med. 1954;40(3):588–99.CrossRefPubMed
72.
Genuth SM, Bennett PH, Miller M, Burch TA. Hyperinsulinism in obese diabetic Pima Indians. Metabolism. 1967;16(11):1010–5.CrossRefPubMed
73.
Pettitt DJ, Moll PP, Knowler WC, Mott DM, Nelson RG, Saad MF, et al. Insulinemia in children at low and high risk of NIDDM. Diabetes Care. 1993;16(4):608–15.CrossRefPubMed
74.
Odeleye OE, de Courten M, Pettitt DJ, Ravussin E. Fasting hyperinsulinemia is a predictor of increased body weight gain and obesity in Pima Indian children. Diabetes. 1997;46(8):1341–5.CrossRefPubMed
75.
Chen YY, Wang JP, Jiang YY, Li H, Hu YH, Lee KO, et al. Fasting plasma insulin at 5 years of age predicted subsequent weight increase in early childhood over a 5-year period—the Da Qing children cohort study. PLoS One. 2015;10(6):e0127389. doi:10.​1371/​journal.​pone.​0127389.CrossRefPubMedPubMedCentral
76.
Sigal RJ, El-Hashimy M, Martin BC, Soeldner JS, Krolewski AS, Warram JH. Acute postchallenge hyperinsulinemia predicts weight gain: a prospective study. Diabetes. 1997;46(6):1025–9.CrossRefPubMed
77.
Arslanian SA, Saad R, Lewy V, Danadian K, Janosky J. Hyperinsulinemia in African-American children: decreased insulin clearance and increased insulin secretion and its relationship to insulin sensitivity. Diabetes. 2002;51(10):3014–9.CrossRefPubMed
78.
Arslanian SA. Metabolic differences between Caucasian and African-American children and the relationship to type 2 diabetes mellitus. Journal of pediatric endocrinology & metabolism : JPEM. 2002;15(Suppl 1):509–17.
79.
Zavaroni I, Zuccarelli A, Gasparini P, Massironi P, Barilli A, Reaven GM. Can weight gain in healthy, nonobese volunteers be predicted by differences in baseline plasma insulin concentration? J Clin Endocrinol Metab. 1998;83(10):3498–500. doi:10.​1210/​jcem.​83.​10.​5178.PubMed
80.
Valdez R, Mitchell BD, Haffner SM, Hazuda HP, Morales PA, Monterrosa A, et al. Predictors of weight change in a bi-ethnic population. The San Antonio Heart Study. Int J Obes Relat Metab Disord. 1994;18(2):85–91.PubMed
81.
Alemzadeh R, Langley G, Upchurch L, Smith P, Slonim AE. Beneficial effect of diazoxide in obese hyperinsulinemic adults. J Clin Endocrinol Metab. 1998;83(6):1911–5. doi:10.​1210/​jcem.​83.​6.​4852.PubMed
82.
Due A, Flint A, Eriksen G, Moller B, Raben A, Hansen JB, et al. No effect of inhibition of insulin secretion by diazoxide on weight loss in hyperinsulinaemic obese subjects during an 8-week weight-loss diet. Diabetes Obes Metab. 2007;9(4):566–74. doi:10.​1111/​j.​1463-1326.​2006.​00645.​x.CrossRefPubMed
83.
Velasquez-Mieyer PA, Cowan PA, Arheart KL, Buffington CK, Spencer KA, Connelly BE, et al. Suppression of insulin secretion is associated with weight loss and altered macronutrient intake and preference in a subset of obese adults. Int J Obes Relat Metab Disord. 2003;27(2):219–26. doi:10.​1038/​sj.​ijo.​802227.CrossRefPubMedPubMedCentral
84.
Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM, et al. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr. 1981;34(3):362–6.PubMed
85.
Isken F, Weickert MO, Tschop MH, Nogueiras R, Mohlig M, Abdelrahman A, et al. Metabolic effects of diets differing in glycaemic index depend on age and endogenous glucose-dependent insulinotrophic polypeptide in mice. Diabetologia. 2009;52(10):2159–68. doi:10.​1007/​s00125-009-1466-9.CrossRefPubMed
86.
Scribner KB, Pawlak DB, Aubin CM, Majzoub JA, Ludwig DS. Long-term effects of dietary glycemic index on adiposity, energy metabolism, and physical activity in mice. Am J Physiol Endocrinol Metab. 2008;295(5):E1126–31. doi:10.​1152/​ajpendo.​90487.​2008.CrossRefPubMedPubMedCentral
87.
• Schwingshackl L, Hoffmann G. Long-term effects of low glycemic index/load vs. high glycemic index/load diets on parameters of obesity and obesity-associated risks: a systematic review and meta-analysis. Nutr Metab Cardiovasc Dis. 2013;23(8):699–706. doi:10.​1016/​j.​numecd.​2013.​04.​008. A systematic review providing evidence for beneficial effects of long-term interventions administering a low glycemic index/load diet with respect to fasting insulin and pro-inflammatory markers such as C-reactive protein CrossRefPubMed
88.
Ebbeling CB, Leidig MM, Feldman HA, Lovesky MM, Ludwig DS. Effects of a low-glycemic load vs low-fat diet in obese young adults: a randomized trial. JAMA. 2007;297(19):2092–102. doi:10.​1001/​jama.​297.​19.​2092.CrossRefPubMed
89.
Hron BM, Ebbeling CB, Feldman HA, Ludwig DS. Relationship of insulin dynamics to body composition and resting energy expenditure following weight loss. Obesity. 2015;23(11):2216–22. doi:10.​1002/​oby.​21213.CrossRefPubMedPubMedCentral
90.
Kotronen A, Vehkavaara S, Seppala-Lindroos A, Bergholm R, Yki-Jarvinen H. Effect of liver fat on insulin clearance. Am J Physiol Endocrinol Metab. 2007;293(6):E1709–15. doi:10.​1152/​ajpendo.​00444.​2007.CrossRefPubMed
91.
•• Erion KA, Berdan CA, Burritt NE, Corkey BE, Deeney JT. Chronic exposure to excess nutrients left-shifts the concentration dependence of glucose-stimulated insulin secretion in pancreatic beta-cells. J Biol Chem. 2015;290(26):16191–201. doi:10.​1074/​jbc.​M114.​620351. Study documents a rapid increase in ß-cell insulin secretion in response to low glucose within 24 h, when cultured in excess nutrients. This basal HI correlates with excess lipid stores in the cell and suggests a lipid mediator for HI CrossRefPubMedPubMedCentral
92.
Vangipurapu J, Stancakova A, Kuulasmaa T, Kuusisto J, Laakso M. Both fasting and glucose-stimulated proinsulin levels predict hyperglycemia and incident type 2 diabetes: a population-based study of 9,396 Finnish men. PLoS One. 2015;10(4):e0124028. doi:10.​1371/​journal.​pone.​0124028.CrossRefPubMedPubMedCentral
93.
Pfutzner A, Kunt T, Hohberg C, Mondok A, Pahler S, Konrad T, et al. Fasting intact proinsulin is a highly specific predictor of insulin resistance in type 2 diabetes. Diabetes Care. 2004;27(3):682–7.CrossRefPubMed
94.
Grill V, Dinesen B, Carlsson S, Efendic S, Pedersen O, Ostenson CG. Hyperproinsulinemia and proinsulin-to-insulin ratios in Swedish middle-aged men: association with glycemia and insulin resistance but not with family history of diabetes. Am J Epidemiol. 2002;155(9):834–41.CrossRefPubMed
95.
Laedtke T, Kjems L, Porksen N, Schmitz O, Veldhuis J, Kao PC, et al. Overnight inhibition of insulin secretion restores pulsatility and proinsulin/insulin ratio in type 2 diabetes. Am J Physiol Endocrinol Metab. 2000;279(3):E520–8.PubMed
96.
Hao Z, Mumphrey MB, Townsend RL, Morrison CD, Munzberg H, Ye J, et al. Reprogramming of defended body weight after Roux-En-Y gastric bypass surgery in diet-induced obese mice. Obesity. 2016;24(3):654–60. doi:10.​1002/​oby.​21400.CrossRefPubMedPubMedCentral
97.
Palleja A, Kashani A, Allin KH, Nielsen T, Zhang C, Li Y, et al. Roux-en-Y gastric bypass surgery of morbidly obese patients induces swift and persistent changes of the individual gut microbiota. Genome Med. 2016;8(1):67. doi:10.​1186/​s13073-016-0312-1.CrossRefPubMedPubMedCentral
98.
Schultes B, Ernst B, Wilms B, Thurnheer M, Hallschmid M. Hedonic hunger is increased in severely obese patients and is reduced after gastric bypass surgery. Am J Clin Nutr. 2010;92(2):277–83. doi:10.​3945/​ajcn.​2009.​29007.CrossRefPubMed
99.
Ahrens M, Ammerpohl O, von Schonfels W, Kolarova J, Bens S, Itzel T, et al. DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery. Cell Metab. 2013;18(2):296–302. doi:10.​1016/​j.​cmet.​2013.​07.​004.CrossRefPubMed
100.
Reed MA, Pories WJ, Chapman W, Pender J, Bowden R, Barakat H, et al. Roux-en-Y gastric bypass corrects hyperinsulinemia implications for the remission of type 2 diabetes. J Clin Endocrinol Metab. 2011;96(8):2525–31. doi:10.​1210/​jc.​2011-0165.CrossRefPubMed

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform. 

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »