Diabetes mellitus type 2

It is characterized by a resistance to insulin action that is initially counteracted by increasing its production. Over time, its production will eventually decrease, leading to loss of glycemic control, which will lead to serious complications in a multitude of organs. It has a worldwide prevalence of around 6% at increasingly younger ages because it is associated with lifestyle.

Type 2 diabetes is mainly the result of the appearance of a resistance to insulin activity in muscle cells, adipocytes (fat) and liver cells. These tissues present alterations in their interaction with insulin, so that they are not able to incorporate glucose into their interior, withdrawing it from the systemic circulation, thus increasing its levels in the blood. Additionally, the pancreas is not able to increase insulin production to the extent necessary in these circumstances to control blood glucose.

The exact reasons for this are unknown. The existence of a genetic-hereditary component is known, but 80% of cases of type 2 diabetes are related to risk factors related mainly, but not exclusively, to lifestyle. Factors that may increase the risk of type 2 diabetes include:

  • Being overweight or obese are major risk factors.
  • Inactivity. Physical activity allows weight control, use of glucose for energy and increases the sensitivity of cells to insulin.
  • Waist circumference. Fat storage primarily in the abdomen, rather than the hips and thighs, is indicative of increased risk.
  • Race and ethnicity. African Americans, Hispanics, Native Americans and Asians, and Pacific Islanders are more likely to develop type 2 diabetes than Caucasians.
  • Blood lipid levels. Elevated triglyceride levels and decreased levels of HDL cholesterol increase the risk of this metabolic disorder.
  • Age. The risk increases with advancing age, especially after age 45.
  • Prediabetes or above-normal glucose levels without actually being diabetes.
  • Pregnancy-related risks. Gestational diabetes or newborn weight greater than 4 kilograms.
  • Polycystic ovary syndrome.

Symptoms

Traditionally this disease was associated with adults, however, due to its important relationship with lifestyle, it is now increasingly associated with children, adolescents and young adults. Symptoms often develop slowly and progressively and may go unnoticed for years until they have diabetes-related health problems. Up to 20% of people with this type of diabetes have signs of complications at the time of diagnosis. When they occur they may include the following:

  • Increased thirst and hunger.
  • Frequent urination.
  • Unintentional and unexplained weight loss.
  • Fatigue.
  • Blurred vision.
  • sores that are slow to heal
  • frequent infections
  • Numbness or tingling in the hands or feet.
  • Darkened areas of skin, usually in the armpits and neck.

When blood glucose levels are very high after advanced progression, severe dehydration can occur, which can lead to mental confusion, drowsiness and seizures, a condition called hyperosmolar hyperglycemic state.

Prevention

Healthy lifestyle choices can help prevent type 2 diabetes even if there is a family history. A healthy lifestyle includes:

  • Eating healthy, high-fiber, low-fat, low-calorie foods, preferably fruits, vegetables, or whole grains.
  • Exercising regularly and avoiding long periods of inactivity by getting up and moving around for a few minutes every 30 minutes or every hour. If you want to lose weight, exercise should be more vigorous.
  • Losing and maintaining a healthy weight can slow the progression of type 2 diabetes.
  • Avoid smoking, as it increases the risk of cardiovascular disease, as well as alcohol and other substance abuse.

There are several clinical studies that show that moderate weight loss and a daily program of half an hour of physical exercise five days a week drastically reduce the risk of developing diabetes. Additionally, the risk is reduced or the development of complications in many organs of long-term hyperglycemia is delayed. Such is the case of retinopathy on the ocular retina, nephropathy due to kidney damage, neuropathy due to central nervous system involvement, or vasculopathies that lead to an increased risk of cardiovascular accidents, arteriosclerosis, or early heart disease.

The prevention of cardiovascular risk in diabetes is of particular relevance, for which it is additionally recommended to control the other cardiovascular risk factors, especially blood pressure (normal BP: 130/80 mmHg) and cholesterol (LDL<100 mg/dL, HDL>50 mg/dL and triglycerides<150 mg/dL). Similarly, ongoing assessment of blood glucose levels is recommended to confirm that they are under adequate control by determining glycosylated hemoglobin (HbA1C) which provides long-term information and fasting blood glucose (before meals 70-130 mg/dl).

Number of observed variants

13.5 million variants

Number of risk loci

514 loci

Genes analyzed

ABCB10 ABCC5 ABCC8 ABL2 ABO ACE ACSL1 ACTN1 ADAMTS9 ADAMTSL3 ADCY5 ADRB1 AFF3 AKAIN1 ALDH1A2 ALKBH3 AMFR AMN ANKDD1B ANKRD55 ANPEP AOAH AOC1 AOPEP APIP APOE APOLD1 ARAP1 ARID2 ARID4A ARID5B ARL15 ARL4D ARMH4 ARNTL ARPP21 ARVCF ATP2A1 ATP8B2 AUTS2 AZIN1 BAK1 BBIP1 BCL11A BCL2 BCL2L11 BDNF BEND3 BEND7 BMP8A BMPR2 BPTF BRAF BRD3OS BTRC C2CD4A C3orf70 CALCR CASR CAST CBX1 CCAR2 CCDC88B CCDC92 CCDC9B CCND1 CCNH CD101 CDC14C CDC7 CDH7 CDKAL1 CDKL2 CDKN1C CDKN2B CEBPB CELF4 CENPW CEP120 CEP68 CKB CKMT1B CLEC14A CMIP CNTNAP2 COL27A1 CPNE4 CRHR2 CRTC1 CRY2 CRYBA1 CRYBA2 CSPG5 CTBP1 CTRB2 CTTNBP2 CUL1 CWH43 CYTH1 DCAF12 DDC DDX20 DEPDC5 DGKB DGKD DHFR2 DLEU7 DLK1 DMAC1 DMRT2 DNAH7 DNMT3A EBF1 EBF2 EGFL8 EIF2S2 ELAVL2 EML2 EMSY EP400 EPO ERBB4 ERLIN1 ERN1 ETAA1 ETS1 ETV1 EVA1B EYA1 EYA2 FADS2 FAF1 FAIM2 FAM227B FAM234A FANCL FBRSL1 FBXL22 FBXW7 FCGRT FGFR3 FIBCD1 FIGNL1 FOCAD FOXA2 FOXK1 FOXP1 FRAT2 FRRS1L FSD2 FTO FXYD2 GALNT3 GBA2 GCDH GCK GCKR GDF6 GINS2 GIP GLI2 GLIS3 GLP2R GLRA1 GNAS GNPDA2 GOLIM4 GP2 GPC5 GPR26 GPSM1 GRB14 GRID1 GRP GSAP GTF2I GUCY1B1 H1-7 H2BC8 HACL1 HCN1 HDAC9 HEY2 HHEX HIVEP2 HLA-G HMBS HMG20A HMGA2 HNF1A HNF1B HNF4A HORMAD2 HOXC5 HPS1 HS6ST3 HSD17B1 HSF1 HSPA12A ID4 IFT52 IFT80 IGF1R IGF2BP2 IKBKE IKZF2 IL20RA IL34 INSR IRS1 IRS2 IRX3 ISCA2 ITGA1 JADE2 JARID2 JAZF1 JMY KBTBD6 KCNH7 KCNJ12 KCNK16 KCNK17 KCNU1 KCTD8 KDM3A KDM4B KIAA1522 KIF3C KL KLF14 KLHL42 KLLN KMT2E KPNA3 KSR2 L1TD1 L3MBTL2 L3MBTL3 LAMA1 LAMC1 LARP1B LCORL LDHB LEPR LIN7A LINGO2 LMF1 LONRF1 LPL LPP LRFN2 LRMDA LRRC1 LRRC66 LRRC74A LRTM1 LTBP3 LTK MACIR MAFF MAGI2 MAML3 MAP2K7 MBNL1 MC4R MDFIC2 MDM4 MED23 MED27 MEOX2 METAP2 MFHAS1 MGAT1 MNAT1 MOB1B MPHOSPH9 MPPED2 MRAS MRPS30 MSANTD1 MSRA MTMR2 MTNR1B MTOR MYC MYCN MYO5C NACAD NAP1L5 NCOA7 NDST2 NDUFAF6 NEDD1 NEGR1 NELL1 NEUROD2 NEUROG3 NFAT5 NFATC2 NFIB NHSL1 NKX6-3 NLGN1 NMI NOL4 NOP2 NOS1 NOTCH2 NPAS3 NPC1 NR5A2 NRBF2 NRP1 NRXN3 NSUN3 NTAN1 NUAK1 NUDT5 NUP160 NUP54 NUS1 OLFM4 OMG OR4A47 OR4C12 OR5B3 OR5D18 PARD3B PARP8 PCBD1 PCCB PCDH17 PCDH9 PCGF3 PDCD4 PDE3A PDGFC PDLIM3 PDZRN4 PENK PEPD PFN1 PGM1 PHF13 PI16 PIGC PIK3C3 PIK3R1 PIM3 PKHD1 PKLR PLEKHA1 PLEKHM3 PLXND1 PML PNOC PNPLA3 PODXL POU3F3 POU5F1 PPARG PPP4R3A PRC1 PRDM5 PRICKLE1 PRIM1 PRIMA1 PRKD1 PROX1 PSAT1 PSMC2 PSMD6 PTP4A1 PTPN9 PURG QKI QSER1 RAB24 RAB3C RANBP17 RASEF RASGRP1 RBM6 RBMS1 RBMS3 RDH14 REV3L RFT1 RFX3 RGMA RGS17 RNF6 ROBO2 RPL10L RPL13 RPTOR RRAGA RREB1 RSPO3 RTN4 RUNX2 RWDD3 SAE1 SAT2 SBF2 SCD5 SCLT1 SEC16B SEC23IP SEPTIN14 SETD5 SGCG SGCZ SGIP1 SHISA4 SHQ1 SHROOM3 SIDT1 SINHCAF SKOR1 SLC12A8 SLC16A11 SLC16A7 SLC1A2 SLC22A3 SLC25A12 SLC25A34 SLC2A2 SLC30A8 SLC38A9 SLC39A11 SLC39A8 SLC41A1 SLC7A5 SLC9B1 SLCO4A1 SLIT2 SLX4 SMARCAD1 SMIM29 SP9 SPHKAP SPRY2 SREBF1 SRP54 SSPN ST6GAL1 STAU2 STEAP2 STK17B STK31 STK35 STRN STXBP6 SUGCT SV2A SYT10 TAT TBCE TCF12 TCF19 TCF3 TCF4 TCF7L2 TENT5C TET1 TET2 TEX29 TFAP2B TFRC TH THADA THBS1 TLE1 TLE4 TM4SF4 TM6SF2 TMBIM1 TMEM106B TMEM154 TMEM161B TMEM18 TMEM219 TMEM81 TMEM87B TNKS TNRC6B TOM1 TP53INP1 TPCN2 TRIM27 TRIM32 TRIM63 TRIM66 TRPS1 TRPV5 TSC22D2 TSEN15 TSHZ2 TSHZ3 TSPAN8 TTN UBE2E2 UBE2E3 UBE2L5 UBE2O UBE3C UGT3A2 UNC5C UNC5D USP49 VEGFA VGLL3 VPS53 VWA5B1 WBP1L WDR11 WDR7 WFS1 WNT8A WSCD2 XKR6 YTHDF2 ZBED3 ZBTB20 ZBTB26 ZBTB38 ZBTB46 ZC3H11B ZC3H13 ZEB2 ZFAT ZFHX3 ZFP64 ZFPM1 ZFPM2 ZHX3 ZMIZ1 ZNF10 ZNF169 ZNF236 ZNF239 ZNF654 ZNF703 ZNF746 ZNF799

Bibliography

Khan MAB et al. Epidemiology of Type 2 Diabetes - Global Burden of Disease and Forecasted Trends. J Epidemiol Glob Health. 2020;10(1):107-111.

Center for Disease Control and Prevention. Diabetes [March 2022]

Mayo Clinic [March 2022]

National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes [March 2022]

Vujkovic M et al. Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis. Nat Genet. 2020 Jul;52(7):680-691.

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