ENDOCRINE PRACTICE Vol 19 No. 3 May/June 2013 497

Review Article

Elena Barengolts, MD

Submitted for publication August 21, 2012

Accepted for publication December 12, 2012

From the Section of Endocrinology, Department of Medicine, University

of Illinois Medical Center and Jesse Brown VA Medical Center, Chicago,

Illinois.

Address correspondence to Dr. Elena Barengolts, Department of Medicine,

Section of Endocrinology, MC 640, 1819 West Polk Street, Chicago, IL 60612.

E-mail: eibareng@uic.edu.

Published as a Rapid Electronic Article in Press at http://www.endocrine

practice.org on January 21, 2013. DOI:10.4158/EP12263.RA

To purchase reprints of this article, please visit: www.aace.com/reprints.

Copyright © 2013 AACE.

ABSTRACT

Objective: To review the role of human large bowel

microbacteria (microbiota) in the glucose homeostasis, to

address vitamin D (VD) and prebiotics interactions with

microbiota, and to summarize recent randomized clinical

trials (RCTs) of VD and prebiotics supplementation in pre-

diabetes (PreDM) and type 2 diabetes mellitus (T2DM).

Methods: Primary literature was reviewed in the fol-

lowing areas: composition and activity of human micro-

biota associated with PreDM and T2DM, interactions

between microbiota and glucose homeostasis, the interac-

tion of microbiota with VD/prebiotics, and RCTs of VD/

prebiotics in subjects with PreDM or T2DM.

Results: The human microbiota is comprised of 100

trillion bacteria with an aggregate genome that is 150-fold

larger than the human genome. Data from the animal mod-

els and human studies reveal that an “obesogenic” diet

results into the initial event of microbiota transformation

from symbiosis to dysbiosis. The microbial antigens, such

as Gram(-) bacteria and lipopolysaccharide (LPS), trans-

locate to the host interior and trigger increased energy

harvesting and Toll-like receptor (TLR) activation with

VXEVHTXHQW�LQÁDPPDWRU\�SDWKZD\V�VLJQDOLQJ��7KH�´GRXEOH�

hit” of steatosis (ectopic fat accumulation) and “–itis”

�LQÁDPPDWLRQ��DQG�FRQWULEXWLRQ�RI�´FRULVNVµ��H�J���YLWDPLQ�'� GHÀFLHQF\� >9''@�� DUH� UHTXLUHG� WR� DFWLYDWH� PROHFXODU�signaling, including impaired insulin signaling and secre-

tion, that ends with T2DM and associated diseases. Dietary

changes (e.g., prebiotics, VD supplementation) may ame-

liorate this process if initiated prior to the process becom-

ing irreversible.

Conclusion: Emerging evidence suggests an impor-

tant role of microbiota in glucose homeostasis. VD sup-

plementation and prebiotics may be useful in managing

PreDM and T2DM. (Endocr Pract. 2013;19:497-510)

Abbreviations:1,25D = 1,25-dixydroxyvitamin D; ApoE = apolipopro-

tein E; GutM = gut (large bowel) microbiota; HOMA = homeostasis model of assessment; LPS = lipopoly-

saccharide; PreDM = prediabetes; RCT = randomized

clinical trial; TLR = toll-like receptors; TNF-_�= tumor

necrosis factor-_; VD = vitamin D; VDD = vitamin D

GHÀFLHQF\��VDR = vitamin D receptor

INTRODUCTION

The process of deterioration of normal glucose toler-

ance into prediabetes (PreDM) and type 2 diabetes melli-

tus (T2DM) involves the contribution of “nature,” such as

LQWHUQDO��QRQPRGLÀDEOH� IDFWRUV� �JHQHWLF�EDFNJURXQG��DJH��DQG�JHQGHU��DQG�´QXUWXUH�µ�ZKLFK�DUH�H[WHUQDO��PRGLÀDEOH�factors. Among the external risk factors, the western diet

�KLJK� IDW�� REHVLW\�SURQH�� DQG� YLWDPLQ�'� �9'�� GHÀFLHQF\�(VDD) are important (1,2). Emerging evidence suggests

WKDW� DQRWKHU� LPSRUWDQW� H[WHUQDO� LQÁXHQFH� RQ� WKH� SDWKR-

physiology of glucose homeostasis may be the large bowel

(gut) microbial community (microbiota) (3-10). Over

the past 10 years, there has been an explosion of knowl-

edge; the number of published papers; PubMed articles

with the key word “microbiota” increased exponentially

from 121 (2002) to 2,234 (2012), and those with the key

498

word “human microbiota” grew from 74 (2002) to 1,324

(2012). The complete composition and function of the gut

microbiota (GutM) is still unknown, but it is proposed to

FRQWULEXWH�WR�WKH�ORZ�JUDGH�LQÁDPPDWLRQ�WKDW�SOD\V�D�VXE-

stantial role in the dysregulation of normal glucose toler-

ance into PreDM and T2DM (5-10). The complexity of the

SURFHVV�QRWZLWKVWDQGLQJ��WKHUH�PD\�EH�VLJQLÀFDQW�LQWHUDF-tions between GutM, dietary components (such as prebiot-

ics and VD), and glucose homeostasis suggesting that diet

enrichment or supplementation with prebiotics and VD

may improve glucose homeostasis.

This article will review the role of GutM in the patho-

genesis of prediabetes and T2DM, address how VD and

prebiotics interact with GutM, and summarize the recent

randomized clinical trials (RCTs) of VD and prebiotics

supplementation in PreDM and T2DM.

Gut Microbiota Composition and Function In Prediabetes and Type 2 Diabetes Mellitus

Recent studies demonstrate that the diverse microor-

ganisms that colonize the body at birth live on mucosal sur-

faces and in the lumen of the human large bowel and exist

LQ�EHQHÀFLDO�V\PELRWLF�UHODWLRQVKLSV�ZLWK�WKHLU�KRVW��������%DFWHULD�PDNH�XS�PRVW�RI�WKH�ÁRUD�DQG�XS�WR�����RI�WKH�dry mass of the feces (7). The GutM is comprised of 100

trillion bacteria (10-fold the number of cells in the human

body), and the genomes of these bacteria (microbiome)

have 150 times more genes than the human genome (3,4).

Multiple molecular methods, including quantitative poly-

merase chain reaction PCR, barcoded pyrosequencing, and

SK\ORJHQHWLF�PLFURDUUD\V�RI���6�U51$�KHOSHG�WR�JHQHUDWH�D�FRPSUHKHQVLYH�PLFURELDO�FRPPXQLW\�SURÀOH��7KLV�SURÀOH�VKRZV�WKDW�PRUH�WKDQ�����RI�PLFURELRWD�DUH�DQDHUREHV��DQG�����FRQWDLQ�VHYHUDO�IDPLOLHV��SK\OD��LQFOXGLQJ�Firmicutes

������� Bacteroidetes� ������� Proteobacteria� ������ DQG�Actinobacteria� ����� ���������7KH� KXPDQ� KRVW� SURYLGHV� D�nutrient-rich habitat and impacts GutM survival by dietary

composition (5,9,10) and the use of prebiotics (11-13), pro-

biotics (13,14), and antibiotics (14). Reciprocally, GutM

HQ]\PH� DFWLYLWLHV� DUH� LPSRUWDQW� IRU� FDUFLQRJHQ� GHWR[LÀ-

cation and facilitating nutrient absorption, metabolizing

YLWDPLQV��GUXJV��DQG�HQGRJHQRXV�KRUPRQHV����������������suggesting that GutM may be a major player in human dis-

HDVH��LQIHFWLRQ��LQÁDPPDWLRQ��DOOHUJ\��FDQFHU��REHVLW\��DQG�diabetes) and possibly longevity (3-5,7-17).

There are multiple convincing lines of evidence of

GutM involvement in glucose homeostasis (Table 1) (9,18-

32). The data from in vitro experiments and in vivo animal

models (knockout, germ-free, and humanized gnotobi-

otic mice) helped to elucidate the mechanisms of glucose

homeostasis regulation by GutM (Tables 1 and 2) (33-44)

and reciprocal changes produced by the western “obeso-

genic” diet that alter the nutrients available to GutM and

result in detrimental qualitative and quantitative dysbio-

sis of the GutM ecosystem with preferential increase in

Gram(-) bacteria (5,9,10,18,21,22).

Particularly revealing in elucidating the contributions

of GutM to human biology and pathobiology was studying

WKH�KXPDQL]HG�JQRWRELRWLF�PRXVH�PRGHO�� D�ZHOO�GHÀQHG��representative animal model of the human gut ecosystem

created by transplanting human fecal microbial commu-

nities into wild-type germ-free mice (10). In this model,

switching from a low-fat, polysaccharide-rich “healthy”

plant diet to a high-fat, high-sugar “obesogenic” diet

shifted GutM ecosystem, metabolic pathways, and gene

expression within a single day, and after 2 weeks the “obe-

sogenic” diet-fed mice almost doubled their body fat (10),

suggesting that “obesogenic GutM” had increased capacity

to harvest energy (9,10). Furthermore, this trait was trans-

missible by GutM: the germ-free mice colonized with an

“obesogenic GutM” doubled their body fat compared to

mice colonized with a “lean GutM” despite consuming the

exact same diet (9,10). Similarly, transplantation of GutM

from mice with metabolic syndrome and insulin resistance

to the wild-type germ-free mice resulted in the transmis-

sion of insulin resistance to the recipient mice (8).

GutM dysbiosis resulted in increased production of

lipopolysaccharide (LPS), a molecule from the outer mem-

brane of Gram(-) bacteria that disrupted mucosal immunity,

breeched the mucosal barrier, acquired access to the inte-

ULRU�RI�WKH�KRVW��DQG�DFWLYDWHG�LQÁDPPDWLRQ�DQG�V\VWHPLF�immunity (Tables 1 and 2). In a mouse model, LPS was

LGHQWLÀHG� DV� D� FDXVDWLYH� WULJJHULQJ� IDFWRU�RI� WKH�RQVHW� RI�obesity, insulin resistance, and diabetes (5). In this model,

the usual diet increased or decreased circulating LPS during

the fed or fasted state, respectively. In contrast, a high-fat

diet chronically increased LPS by 2 to 3 times, a threshold

WKDW�ZDV�GHÀQHG�E\�WKH�DXWKRUV�DV�PHWDEROLF�HQGRWR[HPLD�(for comparison, sepsis and other infections would increase

circulating LPS by 10 to 50 times). Importantly, a high-fat

diet increased the proportion of an LPS-generating GutM,

as well as endogenous LPS production proportionally to

the amount of dietary fat and enhanced the absorption of

orally administered LPS (5). When metabolic endotoxemia

was induced through continuous subcutaneous LPS infu-

sion, fasted glycemia and insulinemia and whole-body,

liver, and adipose tissue weight gain increased to a similar

extent as in high-fat-diet mice. Both endogenous and exog-

enous LPS caused insulin resistance acting via CD14 (a

protein from the Cluster of Differentiation group that acts

as a co-receptor for LPS along with TLR-4, LPS binding

SURWHLQ�� DQG�0'�� SURWHLQ��� 0DFURSKDJH� LQÀOWUDWLRQ� ZDV�higher in adipose tissue of mice fed a high-fat diet and in

mice infused with LPS, and this effect was not observed

in the absence of CD14 (5). The authors suggested that

/36�PLJKW�EH�D�QHZO\�LGHQWLÀHG�LQÁDPPDWRU\�IDFWRU�IURP�

499

GutM, which upon binding to its receptor serves as a vec-

WRU�IRU�WKH�WULJJHULQJ�DQ�´LQÁDPPDWLRQ�LQVXOLQ�UHVLVWDQFH�diabetes” cascade induced by high-fat feeding.

In healthy humans, circulating LPS was associated

with both prevalent and incident T2DM (45) and with fat

DQG�HQHUJ\�LQWDNHV�������DQG�FLUFXODWLQJ�&'���FRUUHODWHG�with insulin resistance (homeostasis model of assessment

>+20$@�,5��� YLVFHUDO� DGLSRVLW\�� DQG�PDUNHUV� RI� LQÁDP-

mation and endothelial dysfunction (47). In patients with

T2DM, genetic polymorphism of CD14 correlated with

insulin sensitivity index (ISI) and endothelial dysfunction

������+HDOWK\� VXEMHFWV� KDG� KLJKHU� IDVWLQJ�/36� DIWHU� FRQ-

suming a fat-enriched meal compared to a control meal (5).

Recently, intravenous LPS infusion to healthy subjects was

used to establish a human model of endotoxemia and sub-

FOLQLFDO�LQÁDPPDWLRQ�������,Q�D�GRXEOH�EOLQG��SODFHER�FRQ-

trolled, random sequence crossover study, low-dose LPS

infusion caused a rapid and transient increase of plasma

WXPRU� QHFURVLV� IDFWRU� �71)��_ (25-fold) and interleukin

�,/���������IROG��IROORZHG�E\�PRGHVW�LQÁDPPDWLRQ�LQ�DGL-pose tissue manifested by induction of mediators of insulin

UHFHSWRU� VLJQDOLQJ� �,/����71)�_, monocyte chemoattrac-

WDQW�SURWHLQ�>0&3��@��IUDFWDONLQH��DQG�VXSSUHVVRU�RI�F\WR-

NLQH�VLJQDOLQJ� >62&6@���DQG� �����0RVW� LPSRUWDQWO\��/36�FDXVHG�VLJQLÀFDQW�LQGXFWLRQ�RI�V\VWHPLF�LQVXOLQ�UHVLVWDQFH�measured by intravenous glucose tolerance (IVGTT, insu-

OLQ�VHQVLWLYLW\�GHFOLQHG�E\������ZLWKRXW�HYLGHQFH�RI�SDQ-

FUHDWLF�EHWD�FHOO�G\VIXQFWLRQ��QR�FKDQJH�LQ�WKH�ÀUVW�SKDVH�RI� WKH� DFXWH� LQVXOLQ� UHVSRQVH� >$,5J@� LQGH[��� &RQVLVWHQW�ZLWK� WKH� ,9*77� GDWD�� LQVXOLQ� UHVLVWDQFH� E\� +20$�,5�LQFUHDVH� E\� ���� ZKLOH� +20$�%� ZDV� XQFKDQJHG� ������Bariatric surgery in morbidly obese patients with and with-

RXW�GLDEHWHV�UHVXOWHG�LQ�VLJQLÀFDQW�FKDQJHV�LQ�*XW0�DIWHU���DQG���PRQWKV�DQG�OHG�WR�PHWDEROLF�SURÀOH�LPSURYHPHQWV��including blood glucose, glycated hemoglobin A1C, insu-

OLQHPLD��+20$�,5��OHSWLQ��DQG�DGLSRQHFWLQ�������,Q�WKHVH�

Table 1Human Studies of the Major Interactions Between the Gut Microbiota

and Glucose Metabolism: Data from Normal Weight, Obese, and Diabetic Patients

Population Major changes in human microbiota composition and activity

+HDOWK\��QRUPDO�weight

Increased calorie intake from 2400 to 3400 kcal/d lead to increased absorption ~150 kcal resulting

���LQWR�LQFUHDVHG�)LUPLFXWHV��a�����DQG�GHFUHDVHG�%DFWHURLGHWHV��a���������Decreased calorie intake from 3400 to 2400 kcal/d lead to decreased absorption ~150 kcal resulting

���LQWR�LQFUHDVHG�%DFWHURLGHWHV��a�����DQG�GHFUHDVHG�)LUPLFXWHV��a���������,QFUHDVHG�LQÁDPPDWRU\�PDUNHUV��,/����71)�_, MCP-1, CX3CL1) in adipose tissue after

LPS IV (19)

/36��FRUUHODWHG�ZLWK�,16�����Obese 'HFUHDVHG�RYHUDOO�*XW0�GLYHUVLW\��GHFUHDVHG�)LUPLFXWHV�DQG�%LÀGREDFWHULD� variable Bacteroidetes

���DQG�$UFKDHD��PHWKDQRJHQV��LQ�2%�YV��&21�����������'HFUHDVHG�%LÀGREDFWHULD�LQ�QHRQDWHV�RI�2:�PRWKHUV and associated with obesity later in

childhood (24)

Increased Bacteroides and Proteobacteria and decreased Firmicutes with wt loss diet (24,25)

���RU�EDULDWULF�VXUJHU\�����*XW0�SURÀOH�FRUUHODWHG�ZLWK�,16�VHQVLWLYLW\�����

LPS: increased LPS after a high fat meal (28); LPS predicted by fat and energy intakes (18);

���/36�FRUUHODWHG�SRVLWLYHO\�ZLWK�,16������DQG�7*�������DQG�GLG�QRW�FRUUHODWH�ZLWK�%*�����������RU�+'/�����

T2DM 'HFUHDVHG�RYHUDOO�*XW0�GLYHUVLW\��GHFUHDVHG�)LUPLFXWHV�DQG�%LÀGREDFWHULD��LQFUHDVHG�%DFWHURLGHV����LQ�7�'0�YV��&21��������*XW0�SURÀOH�FRUUHODWHG�ZLWK�%*������DQG�LQÁDPPDWRU\�PDUNHUV�����

/36��LQFUHDVHG�/36�LQ�7�'0�YV��2%�VH[���DQG�DJH�PDWFKHG�&21�������/36�FRUUHODWHG�SRVLWLYHO\����ZLWK�,16���������DQG�7*�QHJDWLYHO\ ZLWK�+'/�������DQG�GLG�QRW�FRUUHODWH�ZLWK�%*��������

$EEUHYLDWLRQV��%*� �EORRG�JOXFRVH��&21� �FRQWUROV��&;�&/�� �IUDFWDONLQH��,16� �FLUFXODWLQJ�LQVXOLQ��,9� �LQWUDYHQRXV�LQIXVLRQ��,/��� �LQWHUOHXNLQ����/36� �FLUFXODWLQJ�OLSRSRO\VDFFKDULGH��0&3��� �PRQRF\WH�FKHPRWDFWLF�SURWHLQ����2%� �REHVH��2:� �RYHU-weight; T2DM = type 2 diabetes mellitus; 7*� �WULJO\FHULGHV��71)�_�= tumor necrosis factor-_; wt = weight.

500

patients, Faecalibacterium prausnitzii, a conserved and

dominant species of the healthy GutM, was directly linked

WR�WKH�UHGXFWLRQ�LQ�ORZ�JUDGH�LQÁDPPDWLRQ�VWDWH�LQGHSHQ-

dently of calorie intake and was negatively associated with

+20$�,5� ������ )LQDOO\�� WUDQVSODQWDWLRQ� RI� *XW0� IURP�lean healthy donors to recipients with metabolic syndrome

improved insulin sensitivity of recipients (median rate of

JOXFRVH�GLVDSSHDUDQFH�LQFUHDVHG�IURP������WR������+mol/

kg/min; P<.05) and increased abundance of butyrate-pro-

ducing GutM (48).

The investigation of the molecular mechanisms of the

effects of LPS on pancreatic beta-cell function showed

that LPS inhibited insulin gene expression and decreased

glucose-induced insulin secretion (39). These deleterious

effects of LPS were mediated through Toll-like receptor

�7/5����DQG�YLD�QXFOHDU�IDFWRU�NDSSD�%��1)�gB) signaling

Table 2Changes Induced in the Host’s Systems Due to the Interactions of as in Table 3 Gut Microbiota With the Nutrients

System Major characteristic changes and related mechanismsEnergy

AT

GI and

Enteroendocrine

Glucose metabolism

Calcium absorption

,QFUHDVHG�H[WUDFWLRQ�RI�HQHUJ\�IURP�GLHW�UHVXOWHG�LQWR�REHVLW\��,16�UHVLVWDQFH�DQG�7�'0�������������3RVLWLYH�FRUUHODWLRQ�EHWZHHQ�*XW0�SURÀOH�DQG�JOXFRVH�LQWROHUDQFH��7*��DQG�PXVFOH�OLSLGV�����

Increased AT mass in various models (e.g., humanized gnotobiotic micea) (5,9-11,21,33)

Activated AT metabolism via SCFA stimulation of GPR (GPR43), PPAR-a (34,35) and intestinal

���)LDI������,QFUHDVHG�$7�LQÁDPPDWLRQ�YLD�/36b�LQGXFHG�VWLPXODWLRQ�RI�7/5���DQG�7/5���OHDGLQJ�WR�1)�gB

���SDWKZD\�DFWLYDWLRQ�DQG�SURGXFWLRQ�RI�,/���DQG�71)�_ in AT from OB and T2DM patients vs.

���OHDQ�&21������

Regulation of GI peptides involved in food intake (GLP-1, GLP-2, PYY, PP, ghrelin, amylin)

(12,33,34) and GI endocannabinoidc and apelinergic// systems (33,35)

Decreased TJ function and increased gut permeability (5,10-12,37) resulting into increased

���DEVRUSWLRQ�RI�*XW0�WR[LQV�DQG�LQFUHDVHG�V\VWHPLF�LQÁDPPDWLRQ��H�J���6WUHSWRFRFFXV�LQWHUPHGLXV����SURGXFHG�D�VSHFLÀF�F\WRO\VLQ��LQWHUPHGLO\VLQ������

Increased total volume, thickness, and crypt branching in colon mucosa (42)

Protection against gut injury and associated colonocyte apoptosis (41)

Increased enteroendocrine cell number (42)

'HFUHDVHG�,16�VHFUHWLRQ�YLD�7/5��DQG�1)�gB signaling in pancreatic islets in vitro (39)

,QFUHDVHG�,16�UHVLVWDQFH�GXULQJ�LQIHFWLRQ������DQG�/36�,9�LQ�PHQ������DQG�LQ�YLYR�PRGHOV�����Dysregulation of obesity- and T2DM-associated systemic immunity that is activated via the

���LQÁDPPDWRU\�FDVFDGH�FRPSRQHQWV��7/5V��1)�gB, cytokines, etc.) (5,19,33,37,41)

Increased calcium absorptionvia mechanism involving SCFA (propionate) (43,44)

$EEUHYLDWLRQV��$7� �DGLSRVH�WLVVXH��%*� �EORRG�JOXFRVH��&21� �FRQWUROV��)LDI� �IDVWLQJ�LQGXFHG�DGLSRVH�IDFWRU��D�FLUFXODWLQJ�OLSRSUR-

tein lipase inhibitor); GI = gastrointestinal; GLP = glucagon-like peptide; GPR = G-protein-coupled receptors; GutM = gut microbiota;

,/��� �LQWHUOHXNLQ����,16� �FLUFXODWLQJ�LQVXOLQ��,9� �LQWUDYHQRXV�LQIXVLRQ��/36� �FLUFXODWLQJ�OLSRSRO\VDFFKDULGH��33$5�a = peroxi-

some proliferator-activated receptor-a��1)�gB = nuclear factor kappa-light-chain-enhancer of activated B cells; OB = obese; OW =

overweight; PP = pancreatic polypeptide; PYY = peptide YY; SCFA = short-chain fatty acids (acetate, butyrate, propionate); T2DM =

type 2 diabetes mellitus; 7*� �WULJO\FHULGHV��7-� �WLJKW�MXQFWLRQV��7/5� �7ROO�OLNH�UHFHSWRUV��71)�_ = tumor necrosis factor-_. a +XPDQL]HG�JQRWRELRWLF�PLFH�LV�WKH�PRXVH�PRGHO�RI�WKH�KXPDQ�JXW�HFRV\VWHP�RI�JHUP�IUHH�PLFH�FRORQL]HG�ZLWK�WKH�KXPDQ�JXW� microbiota. b LPS is a molecule from the outer membrane of Gram negative bacteria that disrupts mucosal and systemic immunity. c The endocannabinoid system refers to a group of neuromodulatory lipids and their receptors that are involved in a variety of

physiological processes including appetite, pain-sensation, and mood. //The apelinergic system refers to a peptide Apelin and its

G-protein-coupled APJ receptors that are involved in a variety of physiological processes, including glucose metabolism.

501

in pancreatic islets, suggesting a novel mechanism by

which GutM might affect pancreatic beta-cell function

(39). All these data support but do not prove the emerging

view that GutM might play a causal role in pathogenesis of

insulin resistance, prediabetes, and diabetes.

One of the links in the microbiota-glycemia interac-

tion is the enteroendocrine system and the related hor-

mones, including glucagon like peptide-1 and -2 (GLP-1,

GLP-2) and peptide YY (PYY) secreted by the intestinal

L-cells; ghrelin, secreted by the stomach; amylin and pan-

creatic polypeptide (PP) secreted by the pancreas; and adi-

ponectin and leptin secreted by adipose tissue (Table 2).

These hormones are well known modulators of appetite,

food intake, and glucose and fat metabolism and some of

them (e.g., GLP-2) are involved in regulating gut barrier

function through the expression of tight junction proteins

(49).

Various models were utilized to establish the role of

enteroendocrine system in the microbiota-glycemia con-

nection through manipulation of GutM, including geneti-

cally obese and high-fat diet-induced obese and diabetic

mice and fermentable carbohydrate-enriched (prebiotic)

diets. In the study of genetically obese and high-fat diet-

induced obese and diabetic mice, both obesity and pre-

biotic supplementation caused changes in GutM and the

enteroendocrine system (33). The researchers used multiple

molecular methods to generate comprehensive microbial

FRPPXQLW\� SURÀOHV� DQG� VKRZHG� WKDW� SUHELRWLF� LQWHUYHQ-

tion resulted in a decrease of Firmicutes and an increase

of Bacteroidetes phyla and a change of 102 distinct taxa,

��� RI�ZKLFK� GLVSOD\HG� D� !���IROG� FKDQJH� LQ� DEXQGDQFH��and these changes ameliorated obesity-induced gut per-

meability and metabolic endotoxemia (33). Interestingly,

VRPH� VSHFLÀF� EDFWHULD� ZHUH� LGHQWLÀHG� DV� SRVVLEO\� SOD\-

ing particularly important roles. For example, there was

a very strong correlation between gut permeability and

the abundance of Streptococcus intermedius, known to

SURGXFH� D� VSHFLÀF� F\WRO\VLQ� �LQWHUPHGLO\VLQ�� ����� WKDW�alters intestinal cell tight-junction architecture (33). Also,

Akkermansia muciniphila (A. muciniphila), which is asso-

ciated with healthy colon mucosa, strongly and positively

correlated with the enteroendocrine L-cell number (33).

Of note, A. muciniphila inversely correlated with body

weight in humans, increasing after gastric bypass-induced

weight loss (27). Moreover, prebiotic-induced change in

mice GutM was accompanied by increased colon L-cell

QXPEHU� �a������HQKDQFHG� LQWHVWLQDO�SURJOXFDJRQ�P51$�H[SUHVVLRQ� �a��������� LQFUHDVHG� SODVPD� */3��� OHYHOV��a���������� DQG� LPSURYHG� OHSWLQ� VHQVLWLYLW\� �a���������Prebiotic use counteracted high-fat-induced body weight

gain and fat mass development and resulted in improved

glucose tolerance, decreased plasma triglycerides and mus-

cle lipid content (total, triglycerides, and phospholipids),

and reduced expression of oxidative stress (measured by

1$'3+�R[LGDVH��DQG�LQÁDPPDWRU\��,/���P51$��PDUNHUV�LQ�WKH�FRORQ�������,Q�WKH�VDPH�PRXVH�PRGHO��VLPLODU�EHQHÀ-

FLDO�FKDQJHV�LQ�*XW0��VSHFLÀFDOO\�DQ�LQFUHDVH�LQ�ELÀGREDF-teria and a decrease in lactobacilli) were accompanied by

improved gut barrier integrity, improved metabolic endo-

WR[HPLD� DQG�JOXFRVH� WROHUDQFH�� DQG�GHFUHDVHG� LQÁDPPD-tion and weight (49). Multiple enteroendocrine and other

hormones were studied (GLP-1, PYY, PP, amylin, leptin,

JKUHOLQ��ZLWK�VLJQLÀFDQW�FKDQJHV�REVHUYHG�LQ�*/3����3<<��DQG� OHSWLQ��$QDO\VLV�RI� WKH�FRORQ�JHQH�H[SUHVVLRQ�SURÀOH�showed up-regulation of PYY, peroxisome proliferator-

activated receptor (PPAR)-a, TLR-4, and endocannabinoid

system receptor CB2 genes. The authors postulated that the

observed effects could be related to modulation of GutM,

VXFK�DV�KLJKHU�FRQWHQW�RI�ELÀGREDFWHULD�LQ�WKH�FDHFXP������ A randomized, double-blind, parallel, placebo-con-

trolled trial of fermentable carbohydrates (prebiotic) in

healthy humans showed a threefold increase in gut micro-

bial fermentation, increased satiety, and decreased hunger

and energy intake, whereas postprandial plasma glucose

responses decreased after the standardized meal. These

changes were accompanied by higher serum GLP-1 and

PYY concentrations (12). In overweight and obese adults,

prebiotic supplementation resulted in lower circulating

ghrelin, higher PYY, and improved insulin sensitivity in

the intervention group vs. control (51). The mechanism of

enteroendocrine system action might involve sensing the

presence of bacterial antigens (including LPS) through

TLR and neutralizing intestinal bacteria by releasing che-

mokines and defensins as demonstrated with in vitro and in

vivo models, and by inducing contraction of the muscular

tunica, favoring the emptying of the distal small intestine

(52).

The other systems important in obesity-dysglycemia-

dyslipidemia and implicated in the crosstalk between

GutM and metabolism are the endocannabinoid and ape-

linergic systems, with the former involving a group of

neuromodulatory lipids and their receptors, and the latter

involving a peptide apelin and its G-protein-coupled APJ

receptors (Table 2) (12,27,33-35,49-51). In vitro and in

vivo studies using endocannabinoid system agonists and

antagonists showed that this system linked microbiota with

adipogenesis and glucose metabolism by modulating gut

SHUPHDELOLW\��WLJKW�MXQFWLRQ�SURWHLQV��H[SUHVVLRQ�RI�LQÁDP-

matory markers, markers of adipocyte differentiation, and

adipocyte size and number and via their effects on colon

and adipose tissue cannabinoid receptors, with LPS acting

as a master switch (52). Although causality remains to be

proven, these experiments highlighted the essential role

of the enteroendocrine and endocannabinoid systems in

PLFURELRWD�UHODWHG� PRGXODWLRQ� RI� V\VWHPLF� LQÁDPPDWLRQ�and glucose metabolism.

502

Vitamin D Interaction With Gut Microbiota and Vitamin D Use in Randomized Clinical Trials for

Improving Glucose Homeostasis In humans, active 1,25-dixydroxyvitamin D (1,25D)

can be produced and function in endocrine, paracrine and

autocrine manner. VD system directly or indirectly regu-

ODWHV�DERXW����RI�PRXVH�DQG�KXPDQ�JHQRPH�������LQFOXG-

ing genes involved in glucose homeostasis. The role of

VD in glucose homeostasis is one of the well-established

nonclassical roles of this multipotential vitamin (2). All the

components of the VD system are present in the mucosal

cells lining the large bowel (colonocytes), including VD

receptor (VDR), VD response elements (VDREs), and the

enzymes involved in synthesis and catabolism of active

����'��������� VD interactions with GutM may become yet another

nonclassical function of VD (Table 3) (57-70). There are

several pathways for possible VD and GutM relationships

in the large bowel. VD may contribute to acquisition and

PDLQWHQDQFH� RI� V\PELRWLF� JXW� PLFURÁRUD�� %RWK� 9'� DQG�GutM regulate calcium absorption, cellular tight junctions,

mucosal and systemic immunity, and colonocyte activity

(Tables 2 and 3).

VD-regulated intestinal calcium absorption, the clas-

sical action of VD, occurs predominantly in duodenum

and jejunum and involves active intracellular and passive

paracellular absorption. Similar mechanisms are involved

LQ�DERXW�����RI�FDOFLXP�DEVRUSWLRQ�WKDW�RFFXUV�LQ�WKH�ODUJH�ERZHO� ��������� DQG� WKLV� SURFHVV� LV� HQKDQFHG� E\� *XW0�produced propionic acid (43,44). Calcium plays crucial

role in all physiological functions, and it is possible that

VD and GutM act synergistically to maintain calcium bal-

ance. The tight junctions between the intestinal cells play

an important role in paracellular calcium absorption and

are also an integral component of mucosal immunity. Both

VD and GutM are involved in the regulation of the tight

junctions that establish mucosal barriers of defense against

intestinal pathogens (Tables 2 and 3). These intestinal

pathogens may have developed ways of penetrating the

mucosal barrier to exploit the host’s physiological path-

ways of nutrient absorption (e.g., calcium) as a crucial step

in gaining access to the host’s internal resources. Both VD

and GutM play a role in the regulation and signaling path-

ways of all 3 components (mucosal, innate, and adaptive)

of the immune system (Tables 2 and 3) and act to develop

and maintain self-tolerance by down regulating the adap-

tive immune responses while enhancing the protective

innate immune responses. Similarly, both VD and GutM

have trophic effects on colonocytes (Tables 2 and 3) that

have shown in vitro, in animal models, and in human stud-

LHV�RI� LQÁDPPDWRU\�ERZHO�GLVHDVH�DQG�FRORUHFWDO�FDQFHU��LQFOXGLQJ�JHQHWLF�GDWD��������� A few studies suggested possible interdependence

of microbiota and VD and its role in glycemia. In human

monocytic cells, LPS stimulated secretion of 1,25D via

upregulation of 1_-hydroxylase, a transcription factor

(STAT1_), a coactivator (p300), and chromatin remod-

eling (77). Similarly, LPS activated 1_-hydroxylase in

the kidney (78) and in endothelial cells (79). In a human

colon cancer cells, butyrate (a metabolic product of GutM)

VLJQLÀFDQWO\� LQFUHDVHG�9'5� QXPEHU� DQG� DFWLYLW\� ������YV��FRQWURO���%RWK�EXW\UDWH�������YV��FRQWURO��DQG�����'�������YV��FRQWURO��VLJQLÀFDQWO\�VWLPXODWHG�GLIIHUHQWLDWLRQ�of cells, whereas combined treatment with butyrate and

����'� UHVXOWHG� LQ� D� V\QHUJLVWLF� DPSOLÀFDWLRQ� RI� FHOO� GLI-IHUHQWLDWLRQ� ������� YV�� FRQWURO��� 7KH� UHVSRQVLYHQHVV� WR�LPS of monocytes modulated by 1,25D differed between

T2DM patients and controls (80,81). The direct evidence

of the interaction between GutM, VD, and glucose metabo-

OLVP�FDPH�IURP�DSROLSRSURWHLQ�(�GHÀFLHQW�PLFH��$SR(–/–),

a widely used model of obesity with accelerated athero-

sclerosis. A recent work showed that ApoE–/– mice had

impaired glucose tolerance and insulin signaling; increased

LQWHVWLQDO� SHUPHDELOLW\�� LQÁDPPDWRU\� PHGLDWRUV� �71)�_,

5$17(6��LQWUDFHOOXODU�DGKHVLRQ�PROHFXOH�>,&$0@����DQG�PDFURSKDJH�LQÁDPPDWRU\�SURWHLQ�>0,3@��_ in the colon,

liver, and adipose tissue), and scavenger cells among circu-

ODWLQJ�PDFURSKDJHV��DV�ZHOO�DV�D�VLJQLÀFDQW�LQFUHDVH�LQ�WKH�intestinal expression of VDR. The probiotic bacterial com-

ELQDWLRQ� HIÀFLHQWO\� SUHYHQWHG� LQVXOLQ� UHVLVWDQFH� LQ� WKHVH�ApoE–/– mice, likely acting via transactivation of PPAR-a, Farnesoid-X-receptors (FXR), and VDR (82).

The VDD models highlight importance of VD in the

GutM-glycemia relationship. In the VDD rats, oral VD

VXSSOHPHQWDWLRQ�LPSURYHG�PHWDEROLF�HIÀFLHQF\��OLNHO\�DFW-ing via modulation of GutM; body mass was maintained

but there were increases in food intake (1.8 times), cae-

cum size (1.4-times), short-chain fatty acid (SCFA) pro-

duction, and metabolic rate (83). In a diet-induced VDD

mouse model, 27 genes were up- or downregulated (more

than twofold), and VDD mice had elevated levels (50-

fold) of bacteria in the colonic tissue, suggesting that VDD

dysregulated colonic antimicrobial activity and impaired

GutM ecosystem (57). The activated genes were involved

in containment of enteric bacteria (an angiogenin-4 gene

coding for an antimicrobial protein) and in glucose homeo-

stasis. For example, the carbonyl reductase 3 (CBR3) gene

was downregulated threefold in VDD mice, and genetic

variation in CBR3 conferred risk of T2DM and insulin

resistance, most likely via regulation of adipogenesis (84).

Some other genes included apolipoprotein C-II (a modu-

lator of cardiovascular disease in T2DM) (85); TF3, an

adaptive-response gene induced by various stress signals

relevant to T2DM and involved in insulin gene transcrip-

WLRQ�������DQG�SOHLRPRUSKLF�DGHQRPD�JHQH�OLNH����3ODJO����which is involved in insulin secretion and may be impor-

tant in beta-cell exhaustion in insulin-resistant states (87).

� $OWKRXJK�VXJJHVWLYH��WKH�ÀQGLQJV�REWDLQHG�LQ�WKHVH�LQ�vitro and in vivo animal models cannot be translated into

human clinical settings, and further studies are needed

503

Table 3Changes Induced in the Host’s Systems Due to the Interactions of

Gut Microbiota With Vitamin D and Prebiotics

System Major characteristic changes and related mechanisms

Vitamin D-related changes and mechanisms

GutM composition

GI

,QÁDPPDWLRQ�DQG�LPPXQH�system

Calcium

Reciprocal effects of

GutM on VD

'HFUHDVHG�LQÀOWUDWLRQ�RI�PXFRVD�E\�LQWHVWLQDO�SDWKRJHQV������VDR signaling modulated GutM composition (57,59)

,QFUHDVHG�7-�SURWHLQV��������'HFUHDVHG�JXW�SHUPHDELOLW\������DQG�EDFWHULDO�WUDQVORFDWLRQ�WR�PHVHQWHULF�O\PSK�QRGHV������,QFUHDVHG�FRORQLF�HSLWKHOLXP�SUROLIHUDWLRQ�DQG�GLIIHUHQWLDWLRQ���������

'HFUHDVHG�SURLQÁDPPDWRU\�F\WRNLQHV��H�J���,/����,/����,/����,1)�a��DQG�71)�_����������'HFUHDVHG�KLVWRORJLF�IHDWXUHV�RI�FRORQ�LQÁDPPDWLRQ������,PSURYHG�V\VWHPLF�LPPXQLW\��LQQDWH��YLD�7/5��DQG�12'�V\VWHPV·�DQG�GRZQVWUHDP�1)�gB pathway)

������������DQG�DGDSWLYH��YLD�7��DQG�%�O\PSKRF\WH�IXQFWLRQ�������,PSURYHG�ORFDO�PXFRVDO�LPPXQLW\��������,QFUHDVHG�VHFUHWLRQ�DQG�IXQFWLRQ�RI�DQWLPLFURELDO�SURWHLQV��VXFK�DV�FDWKHOLFLGLQ�������DQJLRJHQLQ���������DQG�GHIHQVLQ������

,QFUHDVHG�FDOFLXP�DEVRUSWLRQ�LQ�WKH�ODUJH�ERZHO�����

*XW0�PHWDEROL]HG�9'�DQDORJV������DQG�*XW0�DIIHFWHG�9'5�H[SUHVVLRQ��GLVWULEXWLRQ��WUDQVFULSWLRQDO�activity, and target gene expression in colonocytes (58)

VDD-related changes and mechanisms

GutM composition

GI

,QFUHDVHG�EDFWHULDO�LQÀOWUDWLRQ�RI�WKH�FRORQ�����IROG������

,QFUHDVHG�K\SHUSODVLD�DQG�K\SHUSUROLIHUDWLRQ�RI�FRORQRF\WHV�����,QFUHDVHG�EHQLJQ�DQG�PDOLJQDQW�QHRSODVPV�LQ�WKH�FRORQ�����

Prebiotic-related changes and mechanismsGutM composition

GI and Enteroendocrine

,QÁDPPDWLRQ�DQG�LPPXQH�system

Calcium

Energy and glucose

metabolism

Reciprocal effects of GutM

on prebiotics

'HFUHDVHG�3URWHREDFWHULD�DQG�)LUPLFXWHV��LQFUHDVHG�%DFWHURLGHWHV�DQG�%LÀGREDFWHULD�����������������9DULDEOH�FKDQJHV�LQ�����GLVWLQFW�WD[D�����RI�ZKLFK�GLVSOD\HG�D����IROG�FKDQJH�LQ�DEXQGDQFH�����

,QFUHDVHG�7-�SURWHLQV��]RQXOD�RFFOXGHQV���DQG�FODXGLQ����DQG�7-�IXQFWLRQ�����,PSURYHG�FU\SW�EUDQFKLQJ�DQG�UHOHDVH�RI�PXFLQV�����,PSURYHG�LQWHVWLQDO�PXFRVDO�PRUSKRPHWU\�����Improved differentiation of stem cells into enteroendocrine L-cells (33,37)

,QFUHDVHG�*/3����*/3����3<<���������������DQG�OHSWLQ�VHQVLWLYLW\�����

'HFUHDVHG�PDFURSKDJH�LQÀOWUDWLRQ�LQ�WKH�DGLSRVH�WLVVXH���������'HFUHDVHG�V\VWHPLF�LQÁDPPDWLRQ�YLD�WKH�HQGRFDQQDELQRLG�V\VWHP�PRGXODWLRQ�����������Improved regulation of the immune system (11,34,37)

Increased calcium absorption via mechanism involving SCFA (propionate) (43,44)

'HFUHDVHG�DGLSRVLW\��ERG\�ZHLJKW��VHUXP�DQG�KHSDWLF�FKROHVWHURO�DQG�LQVXOLQ�UHVLVWDQFH�����

GutM metabolized Prebiotics resulting into increased serum SCFA, breath hydrogen and breath

methane (metabolic products of prebiotics) in healthy and hyperinsulinaemic men (70), in vitro

�����������DQG�LQ�YLYR�DQLPDO�PRGHOV�����������

Abbreviations: GutM = Gut Microbiota; ,1)�a = interferon-a��12'� �QXFOHRWLGH�ELQGLQJ�ROLJRPHUL]DWLRQ�GRPDLQ��12'��FRQWDLQLQJ�SURWHLQV���9'� �YLWDPLQ�'��9''� �YLWDPLQ�'�GHÀFLHQF\��9'5� �YLWDPLQ�'�UHFHSWRU��DQG�DV�LQ�7DEOH���

504

to elucidate causal relationships among GutM, glucose

metabolism, and VD. The available data suggest that VDD

may act as a predisposing or/and precipitating factor that

contributes (with other mechanisms) to destabilization

of GutM, decreased colon cell antimicrobial activity, and

increased mucosal permeability. These events may allow

the intact bacteria and/or bioactive bacterial products (e.g.,

LPS) to translocate from the intestinal lumen to the body’s

interior and induce (after activation of multiple complex

SDWKZD\V�� ORZ�JUDGH� LQÁDPPDWLRQ��ZKLFK� LV�D� VXJJHVWHG�mechanism linking GutM with metabolic disorders, includ-

ing prediabetes and T2DM.

Several RCTs in subjects with prediabetes and T2DM

are underway to prove causality of VD levels in these con-

ditions (90). The results from a few published clinical tri-

als are controversial (Table 4) (89-95) and do not clearly

HVWDEOLVK�WKH�EHQHÀWV�RI�9'�VXSSOHPHQWDWLRQ�IRU�LPSURY-

ing glucose homeostasis, proving the sentiment of Thomas

+HQU\�+X[OH\��ZKR�VDLG��´7KH�JUHDW�WUDJHG\�RI�VFLHQFH�³�the slaying of a beautiful hypothesis by an ugly fact.”

Prebiotics Interaction With Gut Microbiota and Prebiotic Use in Randomized Clinical Trials for

Improving Glucose Homeostasis Prebiotics (11) are nondigestible fermentable food

LQJUHGLHQWV�WKDW�DUH�DEOH�WR�FKDQJH�WKH�JXW�PLFURÁRUD�FRP-

SRVLWLRQ�DQG�RU� DFWLYLW\� LQ� D�ZD\� WKDW� LV�EHQHÀFLDO� WR� WKH�KRVW��7DEOHV���DQG�������������3UHELRWLFV�DUH�QRW�GLJHVWHG�and reach the large bowel where they are fermented by

GutM to produce SCFAs (acetate, propionate, and butyr-

ate), L-lactate, CO2, hydrogen, methane, and other metabo-

lites that regulate downstream metabolic processes in mul-

WLSOH�ZD\V��7KH�EHQHÀFLDO�SURSHUWLHV�RI�SUHELRWLFV�LQFOXGH�their contribution to reducing constipation and weight loss,

improving levels of glucose and lipids, and exerting an anti-

carcinogenic effect (11). The most studied prebiotics are

complex carbohydrates (i.e., fructans and arabinoxylans).

Fructans are polymers of fructose molecules (97),

composed of linear chains of fructose units linked by `

glycosidic bonds and typically terminating in a glucose

unit. There are short- chain (oligofructose) and long-chain

(polyfructose, i.e., inulin and levan) fructans, and they

are typically found in the roots and serve as energy reser-

voirs for many plants instead of starch. An arabinoxylan

is a hemicellulose, a copolymer of two pentose sugars,

arabinose and xylose. It is found in cell walls of plants,

LQFOXGLQJ�FHUHDO�JUDLQ�DQG�FKLHÁ\�VHUYHV�D�VWUXFWXUDO�UROH�(97). Fructans belong to soluble and arabinoxylans belong

WR�VROXEOH�DQG�LQVROXEOH�GLHWDU\�ÀEHUV��%RWK�IUXFWDQV�DQG�arabinoxylans change GutM composition in that they

SURPRWH�WKH�SUROLIHUDWLRQ�RI�EHQHÀFLDO�%LÀGREDFWHULD�DQG�Lactobacilli (Table 3).

The examples of raw natural food particularly rich in

prebiotics (percent content by weight) include chicory root

�a������-HUXVDOHP�DUWLFKRNH��a������EDUOH\��������JDUOLF�

�a������ RQLRQ� �a������ JOREH� DUWLFKRNH� �a����� U\H� EUDQ�RU� JUDLQ� �a�����ZKHDW� EUDQ� �a����� DQG� DVSDUDJXV� ������DQG�H[DPSOHV�RI�FRRNHG�IRRG�DUH�FKRFRODWH������DQG�ZKLWH�EUHDG��a������������ Since Roberfroid introduced the concept of prebiotics

in 1995 (11), in vitro and in vivo models have produced

convincing evidence of the profound effects of prebiot-

ics on energy and glucose homeostasis (Tables 3 and 4).

Some of the mechanisms of these effects remain to be fur-

WKHU�FODULÀHG�EXW�LQFOXGH�WKH�FKDQJH�RI�*XW0�FRPSRVLWLRQ�(e.g., decreased Firmicutes and increased Bacteroidetes),

increased levels of satietogenic gut peptides, decreased

V\VWHPLF� LQÁDPPDWLRQ�� DQG� LPSURYHG� JOXFRVH� WROHUDQFH�(Table 3). These data prompted RCTs that produced prom-

ising but variable results (Table 4) that require further

FRQÀUPDWLRQ�

CONCLUSION

The role of GutM in pathogenesis of prediabetes and

diabetes, as well as the contribution of VD and prebiot-

ics to this process are inadequately understood. Available

data suggest that an “obesogenic” diet leads to the initial

event of microbiota transformation from symbiosis to

dysbiosis. Microbial antigens, such as Gram(-) bacteria

and LPS, translocate to the host interior and trigger TLR

complex activation with subsequent macrophage tissue

LQÀOWUDWLRQ� DQG� LQÁDPPDWRU\� SDWKZD\V� VLJQDOLQJ�� 7KH�“double hit” of steatosis (ectopic fat accumulation) and

´²LWLVµ��LQÁDPPDWLRQ��DQG�FRQWULEXWLRQ�RI�´FR�ULVNVµ��H�J���VDD) are required to activate molecular signaling, includ-

ing impaired insulin signaling and secretion that ends with

diabetes and diseases associated with T2DM (Fig. 1). The

awareness that VDD may play a role only as a contrib-

uting factor helps to understand the failure of recent ran-

domized trials of VD supplementation in prediabetes and

indicates that the search for an appropriate intervention or

intervention combination (e.g., VD and prebiotics) and an

appropriate time window (prior to the process becoming

irreversible) should continue.

The complexity of multidirectional effects and mecha-

nisms of diabetes pathogenesis remains to be elucidated.

In the interim, the current professional society guide-

OLQHV�FDQ�EH�XVHG�IRU�UHFRPPHQGLQJ�9'�DQG�GLHWDU\�ÀEHU�daily intake. For VD, the Institute of Medicine (IOM),

the Endocrine Society, and the American Association of

Clinical Endocrinologists (AACE) Recommended Daily

$OORZDQFHV��5'$V��DUH�����DQG�����,8�GD\�IRU�DJHV�������\HDUV�DQG�����\HDUV��UHVSHFWLYHO\��������,8�GD\�LV�UHFRP-

mended for obese adults, while raising the blood level of

25-hydroxyvitamin D above 30 ng/mL may require 1,500-

������ ,8�GD\� IRU� DOO� DGXOWV� DQG�������� ,8�GD\� IRU� REHVH�DGXOWV��������)RU�ÀEHU��HQGRUVHG�E\�WKH�,20��WKH�$PHULFDQ�Diabetes Association, and other groups) the Recommended

Adequate Intake (RAI) is 25-38 g/day (14 g/1,000 kcal/day)

505

for all adults (101) and 25-50 g/day for T2DM (102), and

these suggestions correspond to the AACE-recommended

7-10 servings/day of “healthful” carbohydrates (1). The

DYHUDJH�LQWDNHV�RI�YLWDPLQ�'�DQG�ÀEHU�DUH�UHSRUWHG�DV��������� ,8�GD\� ������ DQG� �������� J�GD\� ������� UHVSHFWLYHO\��which are both lower than recommended. Interestingly,

the mean serum 25-hydroxyvitamin D concentration in

WUDGLWLRQDOO\�OLYLQJ�SRSXODWLRQV�LQ�(DVW�$IULFD�LV����QJ�P/�

(105) and the estimated (from stable carbon isotope analy-

VLV�RI�KXPDQ�VNHOHWRQV��FRQVXPSWLRQ�RI�LQXOLQ�W\SH�ÀEHUV�E\�WKH�SUHKLVWRULF�KXQWHU�IRUDJHUV�LV�����J�GD\��������7KH�recommendation to increase consumption of VD-rich food

(salmon, mackerel, sardines, herring, and cod liver oil) and

prebiotics (artichokes, onion, garlic, etc.) is expected to

SURYLGH�PXOWLSOH�KHDOWK�EHQHÀWV�DQG�HQVXUH�GHOLYHU\�RI�WKH�best medical care.

Table 4Randomized Clinical Trials (RCT)a of Vitamin D or Prebiotic Supplementation

in Subjects At Risk or With Prediabetes and Type 2 Diabetes Mellitus

Study n PopulationDuration,

weeksTreatment

and testMain glycemic

outcomeOther

outcomes5&7�RI�9LWDPLQ�'�GRVHV��������,8�DQG�GXUDWLRQ�����ZHHNV

Jorde et al (89,90)

+DUULV�HW�DO�����

Mitri et al (92)

YRQ�+XUVW�HW�DO�(93)

Jorde et al (94)

Davidson et al

(95)b

Parnell et al (50)

Malaguarnera

et al ����

330

89

92

81

��

99

48

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24

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1R�FKDQJH��)%*��),16��A1c

1R�FKDQJH��LQFLGHQW�T2DM

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GIP & GLP-1

Decrease: AST, LDL,

&53��71)�_, LPS,

VWHDWRVLV��1$6+�DFWLYLW\�index

Abbreviations: AST = aspartate aminotransferase; BG = blood glucose; BW = body weight; CRP = C-reactive protein; D3 = cholecalciferol; DI = dis-

SRVLWLRQ�LQGH[��H7�'0� �HDUO\�W\SH���GLDEHWHV�PHOOLWXV��)� �IDVWLQJ��),16� �IDVWLQJ�LQVXOLQ��*,3� �JOXFRVH�GHSHQGHQW�LQVXOLQRWURSLF�SHSWLGH��+20$� �KRPHRVWDWLF�PRGHO�DVVHVVPHQW��,16� �LQVXOLQ��,16�5� �LQVXOLQ�UHVLVWDQFH��,16�6� �,16�VHQVLWLYLW\��,16�6HF� �,16�VHFUHWLRQ��,9*77� �LQWUDYHQRXV�JOXFRVH�WROHUDQFH�WHVW��077� �PHDO�WROHUDQFH�WHVW��1$6+� �QRQDOFRKROLF�VWHDWRKHSDWLWLV��2%� �REHVH��2)� �ROLJRIUXFWRVH��2*77� �RUDO�JOXFRVH�WROHUDQFH�WHVW��2:� �RYHUZHLJKW��352� �SURELRWLFV��%LÀGREDFWHULXP�ORQJXP���Z� �ZHHN��RWKHUV�DV�LQ�7DEOHV���DQG���a�5&7�GXUDWLRQ�����ZHHNV�DUH�LQFOXGHG��9LWDPLQ�'�5&7��'�VXSSOHPHQW�GRVHV�DUH�GDLO\�GRVHV�LQ�,8�XQOHVV�VSHFLÀHG��RQO\�5&7�XVLQJ��������,8�GD\� are included. b 9LWDPLQ�'��GRVH�ZDV�FDOFXODWHG�EDVHG�RQ�ERG\�ZHLJKW�DQG�EDVHOLQH����2+�'�OHYHO�DQG�UDQJHG����������������,8�ZHHN��,QVXOLQ�VHQVLWLYLW\�DQG� secretion and disposition index were calculated by multiple methods

506

Fig. 1. The microbiota and T2DM and related diseases. The “obesogenic” diet results into detrimental change

in microbiota, the initial event of pathologic metabolic processes. The “double hit” of steatosis (ectopic fat

DFFXPXODWLRQ��DQG�´²LWLVµ��LQÁDPPDWLRQ��DQG�´FRULVNVµ��H�J���9'�GHÀFLHQF\��DUH�UHTXLUHG�IRU�WKH�SURJUHV-VLRQ�WR�WKH�GLVHDVH��7�'0��&9'��DQG�1$6+��'LHWDU\�FKDQJHV��H�J���SUHELRWLFV��9'�VXSSOHPHQWDWLRQ��PD\�prevent or ameliorate the process if started at the appropriate time prior to the process becoming irrevers-

ible. The ovals represent the “states,” rectangles represent the “processes,” and double lines highlight the

RXWFRPHV��$EEUHYLDWLRQV��&9'� �FDUGLRYDVFXODU�GLVHDVH��/36� �OLSRSRO\VDFFKDULGH��1$6+� �QRQ�DOFRKROLF�steatohepatitis; TLR = Toll-like receptor; VD = vitamin D; VDR = vitamin D receptor.

507

DISCLOSURE

The author has no multiplicity of interest to disclose.

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